Compounds and their methods of use

ABSTRACT

The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including Dravet syndrome or epilepsy are also provided herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/485,581, filed on Aug. 13, 2019; which is a 35 U.S.C. § 371 nationalstage filing of International Application Number PCT/US2018/018044,filed on Feb. 13, 2018; which claims priority to and the benefit of U.S.Provisional Patent Application No. 62/458,317, filed on Feb. 13, 2017,U.S. Provisional Patent Application No. 62/481,468, filed on Apr. 4,2017, and U.S. Provisional Patent Application No. 62/545,549, filed onAug. 15, 2017, each of which is incorporated herein by reference in itsentirety.

BACKGROUND

Sodium ion (Na+) channels primarily open in a transient manner and arequickly inactivated, thereby generating a fast Na+ current to initiatethe action potential. The late or persistent sodium current (INaL) is asustained component of the fast Na+ current of cardiac myocytes andneurons. Many common neurological and cardiac conditions are associatedwith abnormal INaL enhancement, which contributes to the pathogenesis ofboth electrical and contractile dysfunction in mammals (see, e.g.,Pharmacol Ther (2008) 119:326-339). Accordingly, pharmaceuticalcompounds that selectively modulate sodium channel activity, e.g.,abnormal INaL, are useful in treating such disease states.

SUMMARY OF THE INVENTION

Described herein are fused heteroaryl compounds and compositions usefulfor preventing and/or treating a disease, disorder, or condition, e.g.,a disease, disorder, or condition relating to aberrant function of asodium ion channel, e.g., abnormal late sodium current (INaL). In oneaspect, the present disclosure features compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, andZ is independently N or CR′; M is O, C(R^(2a))(R^(2b)), or N(R^(2c)); Ais aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), whereinaryl and heteroaryl are substituted by one or more R³; R′ is hydrogen,alkyl, —OR^(c), or halogen; R¹ is hydrogen, alkyl, carbocyclyl, orheterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁴; each of R^(2a), R^(2b), andR^(2c) is independently hydrogen or alkyl, wherein alkyl is optionallysubstituted by one or more R⁴; each R³ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR^(c), whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁵; each of R⁴ and R⁵ is independently deuterium, alkyl,carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro,—OR^(c), —N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), or —C(O)N(R^(d))₂, whereinalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁷; each R^(c) is independently hydrogen,alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁶; each R^(d) is independently hydrogen oralkyl, wherein each alkyl is optionally substituted by one or more R⁶;or two R^(d), taken together with the atoms to which they are attached,form a ring; each R⁶ is independently alkyl, carbocyclyl, heterocyclyl,halo, cyano, nitro, or —OH; and each R⁷ is independently alkyl, halo, oroxo.

In another aspect, the present disclosure provides a compound of formula(I-1):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the present disclosure provides a compound offormula (I-2):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the present disclosure provides a compound offormula (I-3):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the present disclosure provides a compound offormula (I-4):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the present disclosure provides a compound offormula (I-5):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the present disclosure provides a compound offormula (I-6):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the present disclosure provides a compound offormula (I-7):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a compound disclosed herein or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

In another aspect, the present disclosure provides a method of treatinga neurological disorder or a psychiatric disorder, wherein the methodcomprises administering to a subject in need thereof a compounddisclosed herein or a pharmaceutically acceptable salt thereof or apharmaceutical composition disclosed herein.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing Detailed Description,Examples, and Claims.

DETAILED DESCRIPTION OF THE INVENTION

As generally described herein, the present invention provides compoundsand compositions useful for preventing and/or treating a disease,disorder, or condition described herein, e.g., a disease, disorder, orcondition relating to aberrant function of a sodium ion channel, such asabnormal late sodium current (INaL). Exemplary diseases, disorders, orconditions include a neurological disorder (e.g., epilepsy or anepilepsy syndrome, a neurodevelopmental disorder or a neuromusculardisorder), a psychiatric disorder, pain, or a gastrointestinal disorder.

Definitions Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

As used herein a pure enantiomeric compound is substantially free fromother enantiomers or stereoisomers of the compound (i.e., inenantiomeric excess). In other words, an “S” form of the compound issubstantially free from the “R” form of the compound and is, thus, inenantiomeric excess of the “R” form. The term “enantiomerically pure” or“pure enantiomer” denotes that the compound comprises more than 75% byweight, more than 80% by weight, more than 85% by weight, more than 90%by weight, more than 91% by weight, more than 92% by weight, more than93% by weight, more than 94% by weight, more than 95% by weight, morethan 96% by weight, more than 97% by weight, more than 98% by weight,more than 98.5% by weight, more than 99% by weight, more than 99.2% byweight, more than 99.5% by weight, more than 99.6% by weight, more than99.7% by weight, more than 99.8% by weight or more than 99.9% by weight,of the enantiomer. In certain embodiments, the weights are based upontotal weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, an enantiomerically pure compoundcan be present with other active or inactive ingredients. For example, apharmaceutical composition comprising enantiomerically pure R—compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure R—compound. In certain embodiments, theenantiomerically pure R—compound in such compositions can, for example,comprise, at least about 95% by weight R—compound and at most about 5%by weight S—compound, by total weight of the compound. For example, apharmaceutical composition comprising enantiomerically pure S—compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure S—compound. In certain embodiments, theenantiomerically pure S—compound in such compositions can, for example,comprise, at least about 95% by weight S—compound and at most about 5%by weight R—compound, by total weight of the compound. In certainembodiments, the active ingredient can be formulated with little or noexcipient or carrier.

Compound described herein may also comprise one or more isotopicsubstitutions. For example, H may be in any isotopic form, including ¹H,²H (D or deuterium), and ³H (T or tritium); C may be in any isotopicform, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form,including ¹⁶O and ¹⁸O; and the like.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention. When describing the invention,which may include compounds, pharmaceutical compositions containing suchcompounds and methods of using such compounds and compositions, thefollowing terms, if present, have the following meanings unlessotherwise indicated. It should also be understood that when describedherein any of the moieties defined forth below may be substituted with avariety of substituents, and that the respective definitions areintended to include such substituted moieties within their scope as setout below. Unless otherwise stated, the term “substituted” is to bedefined as set out below. It should be further understood that the terms“groups” and “radicals” can be considered interchangeable when usedherein. The articles “a” and “an” may be used herein to refer to one orto more than one (i.e. at least one) of the grammatical objects of thearticle. By way of example “an analogue” means one analogue or more thanone analogue.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

As used herein, “alkyl” refers to a radical of a straight—chain orbranched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms(“C₁₋₂₀ alkyl”). In some embodiments, an alkyl group has 1 to 10 carbonatoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9carbon atoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1to 8 carbon atoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl grouphas 1 to 7 carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkylgroup has 1 to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, analkyl group has 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments,an alkyl group has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In someembodiments, an alkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). Insome embodiments, an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”).In some embodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”).Examples of C₁₋₆ alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, pentyl, hexyl, and the like.

As used herein, “alkenyl” refers to a radical of a straight—chain orbranched hydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon doublebonds), and optionally one or more carbon-carbon triple bonds (e.g., 1,2, 3, or 4 carbon-carbon triple bonds) (“C₂₋₂₀ alkenyl”). In certainembodiments, alkenyl does not contain any triple bonds. In someembodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like.

As used herein, “alkynyl” refers to a radical of a straight-chain orbranched hydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triplebonds), and optionally one or more carbon-carbon double bonds (e.g., 1,2, 3, or 4 carbon-carbon double bonds) (“C₂₋₂₀ alkynyl”). In certainembodiments, alkynyl does not contain any double bonds. In someembodiments, an alkynyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like.

As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to adivalent radical of an alkyl, alkenyl, and alkynyl group respectively.When a range or number of carbons is provided for a particular“alkylene,” “alkenylene,” or “alkynylene,” group, it is understood thatthe range or number refers to the range or number of carbons in thelinear carbon divalent chain. “Alkylene,” “alkenylene,” and“alkynylene,” groups may be substituted or unsubstituted with one ormore substituents as described herein.

As used herein,“aryl” refers to a radical of a monocyclic or polycyclic(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6,10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbonatoms and zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has six ring carbon atoms(“C₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has tenring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has fourteen ring carbonatoms (“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systemswherein the aryl ring, as defined above, is fused with one or morecarbocyclyl or heterocyclyl groups wherein the radical or point ofattachment is on the aryl ring, and in such instances, the number ofcarbon atoms continue to designate the number of carbon atoms in thearyl ring system. Typical aryl groups include, but are not limited to,groups derived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, coronene, fluoranthene,fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene,indane, indene, naphthalene, octacene, octaphene, octalene, ovalene,penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene,phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene,triphenylene, and trinaphthalene. Particularly aryl groups includephenyl, naphthyl, indenyl, and tetrahydronaphthyl.

As used herein, “heteroaryl” refers to a radical of a 5-10 memberedmonocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 πelectrons shared in a cyclic array) having ring carbon atoms and 1-4ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following:

wherein each Z is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ isindependently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ carbocyclyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of anon—aromatic cyclic hydrocarbon group having from 3 to 10 ring carbonatoms (“C₃₋₁₀ carbocyclyl”) and zero heteroatoms in the non—aromaticring system. In some embodiments, a carbocyclyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In someembodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groupsinclude, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃),cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl(C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and thelike. Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system.

As used herein, “heterocyclyl” or “heterocyclic” refers to a radical ofa 3- to 10-membered non-aromatic ring system having ring carbon atomsand 1 to 4 ring heteroatoms, wherein each heteroatom is independentlyselected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon(“3-10 membered heterocyclyl”). In heterocyclyl groups that contain oneor more nitrogen atoms, the point of attachment can be a carbon ornitrogen atom, as valency permits. A heterocyclyl group can either bemonocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ringsystem such as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non—aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g., heteroalkyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g,.heteroaryl; and the like having from 1 to 5, and particularly from 1 to3 heteroatoms.

As used herein, “cyano” refers to —CN.

As used herein, “halo” or “halogen” refers to fluoro (F), chloro (Cl),bromo (Br), and iodo (I). In certain embodiments, the halo group iseither fluoro or chloro.

As used herein, “haloalkyl” refers to an alkyl group substituted withone or more halogen atoms.

As used herein, “nitro” refers to —NO₂.

As used herein, “oxo” refers to —C═O.

In general, the term “substituted”, whether preceded by the term“optionally” or not, means that at least one hydrogen present on a group(e.g., a carbon or nitrogen atom) is replaced with a permissiblesubstituent, e.g., a substituent which upon substitution results in astable compound, e.g., a compound which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, orother reaction. Unless otherwise indicated, a “substituted” group has asubstituent at one or more substitutable positions of the group, andwhen more than one position in any given structure is substituted, thesubstituent is either the same or different at each position.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, SO₄ ⁻²sulfonateions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions(e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate,tartrate, glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substitutents include, but are notlimited to, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa),—C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂,—SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂,—C(═O)SR^(cc), —C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂,—P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(cc)groups attached to a nitrogen atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1,2, 3, 4, or 5 R^(dd) groups, andwherein R^(aa), R^(bb), R^(cc) and R^(dd) are as defined above.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and Claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other definitions

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Pharmaceutically acceptable salts derived from appropriatebases include alkali metal, alkaline earth metal, ammonium andN⁺(C₁₋₄alkyl)₄ salts. Representative alkali or alkaline earth metalsalts include sodium, lithium, potassium, calcium, magnesium, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

As used herein, a “subject” to which administration is contemplatedincludes, but is not limited to, humans (i.e., a male or female of anyage group, e.g., a pediatric subject (e.g, infant, child, adolescent) oradult subject (e.g., young adult, middle—aged adult or senior adult))and/or a non-human animal, e.g., a mammal such as primates (e.g.,cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats,rodents, cats, and/or dogs. In certain embodiments, the subject is ahuman. In certain embodiments, the subject is a non-human animal. Theterms “human,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition (“prophylactic treatment”).

As used herein, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response. As will beappreciated by those of ordinary skill in this art, the effective amountof a compound of the invention may vary depending on such factors as thedesired biological endpoint, the pharmacokinetics of the compound, thedisease being treated, the mode of administration, and the age, health,and condition of the subject. An effective amount encompassestherapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

Compounds

In one aspect, the present invention features a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, andZ is independently N or CR′; M is O, C(R^(2a))(R^(2b)), or N(R^(2c)); Ais aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), whereinaryl and heteroaryl are substituted by one or more R³; R′ is hydrogen,alkyl, —OR^(c), or halogen; R¹ is hydrogen, alkyl, carbocyclyl, orheterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁴; each of R^(2a), R^(2b), andR^(2c) is independently hydrogen or alkyl, wherein alkyl is optionallysubstituted by one or more R⁴; each R³ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR^(c), whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁵; each of R⁴ and R⁵ is independently deuterium, alkyl,carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro,—OR^(c), —N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), or —C(O)N(R^(d))₂, whereinalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁷; each R^(c) is independently hydrogen,alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁶; each R^(d) is independently hydrogen oralkyl, wherein each alkyl is optionally substituted by one or more R⁶;or two R^(d), taken together with the atoms to which they are attached,form a ring; each R⁶ is independently alkyl, carbocyclyl, heterocyclyl,halo, cyano, nitro, or —OH; and each R⁷ is independently alkyl, halo, oroxo.

In some embodiments, X is CR′(e.g., CH). In some embodiments, Y isCR′(e.g., CH). In some embodiments, Z is CR′(e.g., CH). In someembodiments, each of X, Y, and Z is independently CR′(e.g., CH).

In some embodiments, X is N. In some embodiments, X is N and Y isCR′(e.g., CH). In some embodiments, X is N and Z is CR′(e.g., CH). Insome embodiments, X is N and each of X and Y is independently CR′(e.g.,CH).

In some embodiments, Y is N. In some embodiments, Y is N and X isCR′(e.g., CH). In some embodiments, Y is N and Z is CR′(e.g., CH). Insome embodiments, Y is N and each of X and Z is independently CR′(e.g.,CH).

In some embodiments, Z is N. In some embodiments, Z is N and X isCR′(e.g., CH). In some embodiments, Z is N and Y is CR′(e.g., CH). Insome embodiments, Z is N and each of X and Y is independently CR′(e.g.,CH).

In some embodiments, M is O.

In some embodiments, M is C(R^(2a))(R^(2b)). In some embodiments, M isC(R^(2a))(R^(2b)) and each of R^(2a) and R^(2b) is independentlyhydrogen.

In some embodiments, M is N(R^(2c)). In some embodiments, M is N(R^(2c))and R^(2c) is hydrogen or alkyl (e.g., methyl or ethyl).

In some embodiments, A is aryl. In some embodiments, A is 6-memberedaryl (e.g., phenyl). In some embodiments, A is phenyl substituted by 1R³. In some embodiments, A is phenyl substituted by 1 R³ in the paraposition.

In some embodiments, A is heteroaryl. In some embodiments, A is6-membered heteroaryl. In some embodiments, A is nitrogen-containingheteroaryl. In some embodiments, A is pyridyl. In some embodiments, A ispyridyl substituted by 1 R³. In some embodiments, A is pyridyl issubstituted by 1 R³ in the para position.

In some embodiments, R³ is alkyl or —OR^(c). In some embodiments, R³ is—OR^(c). In some embodiments, R^(c) is alkyl. In some embodiments, R^(c)is alkyl substituted by one or more R⁶. In some embodiments, R⁶ is halo.In some embodiemnts, R³ is —OCH₃, —OCF₃, or —OCH₂CF₃. In someembodiemnts, R³ is —OCF₃.

In some embodiments, R³ is alkyl. In some embodiments, R³ is alkylsubstituted with R⁵ (e.g., 1 R⁵). In some embodiments, R⁵ is —OR^(c). Insome embodiments, R³ is —CH₂OCH₃.

In some embodiments, R¹ is hydrogen or alkyl. In some embodiments, R¹ ishydrogen.

In some embodiments, R¹ is alkyl. In some embodiments, R¹ is C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, R¹ isunsubstituted C₁₋₆ alkyl (e.g., unsubstituted methyl, unsubstitutedethyl, unsubstituted propyl, or unsubstituted isopropyl). In someembodiments, R¹ is C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, orisopropyl) substituted with 1-4 R⁴. In some embodiments, R¹ is C₁₋₄alkyl substituted with 1-4 R⁴.

In some embodiments, R⁴ is deuterium, halo, —OR^(c), oxo, carbocyclyl,heteroaryl, —C(O)OR^(c), or —C(O)N(R^(d))₂. In some embodiments, R4 isdeuterium. In some embodiments, R¹ is CD₃ or CD₂CD₃.

In some embodiments, R⁴ is halo (e.g., fluoro). In some embodiments, R¹is —CH₂CF₃ or CH₂CHF₂.

In some embodiments, R⁴ is —OR^(c) (e.g., —OH or —OCH₃). In someembodiments, le is —CH₂CH₂OCH₃, CH₂CH₂OH, CH₂CH₂CH(OH)CH₃, CH₂CH₂CH₂OH,or CH₂CH₂CH₂OCH₃.

In some embodiments, R⁴ is carbocyclyl (e.g., cyclopropyl). In someembodiments, R¹ is —CH₂CH₂-cyclopropyl or —CH₂-cyclopropyl. In someembodiments, R⁴ is heterocyclyl (e.g., tetrahydropyranyl,tetrahydrofuranyl).

In some embodiments, R¹ is —CH₂-tetrahydropyranyl or—CH₂-tetrahydrofuranyl.

In some embodiments, R⁴ is heteroaryl (e.g., oxadiazolyl, pyrimidinyl).In some embodiments, R⁴ is heteroaryl (e.g., oxadiazolyl) substituted by1-4 R⁷. In some embodiments, R¹ is —CH₂CH₂-5-methyl-1,3,4-oxadiazole. Insome embodiments, R⁴ is —C(O)OR^(c) (e.g., —C(O)OH). In someembodiments, R¹ is —CH₂C(O)OH.

In some embodiments, R⁴ is —C(O)N(R^(d))₂ (e.g., C(O)—NH(CH₃)₂,C(O)—NHCH(CH₃)₂, C(O)—NH(CH₃)(CH₂CH₃), C(O)N(CH₃)CH₂CF₃, orC(O)—N-pyrrolidinyl). In some embodiments, R¹ is —CH₂C(O)NHCH(CH₃)₂ or—C(O)—N-pyrrolidinyl.

In another aspect, the present invention features a compound of Formula(I-1):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

M is O, C(R^(2a))(R^(2b)),) or N(R^(2c)); A is aryl or heteroaryl (e.g.,6-membered aryl or heteroaryl), wherein aryl and heteroaryl aresubstituted by one or more R³;

R′ is hydrogen, alkyl, —OR^(c), or halogen;

R¹ is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁴;

each of R^(2a), R^(2b), and R^(2c) is independently hydrogen or alkyl,wherein alkyl is optionally substituted by one or more R⁴;

each R³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵;

each of R⁴ and R⁵ is independently deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —OR^(c),—N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), —S(O)₂—R^(e), —S(O)₂N(R^(d))₂, or—C(O)N(R^(d))₂, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁷;

each R^(c) is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶;

each R^(d) is independently hydrogen or alkyl, wherein each alkyl isoptionally substituted by one or more R⁶; or two R^(d), taken togetherwith the atoms to which they are attached, form a heterocyclyloptionally substituted with —OH, alkoxy, or alkyl optionally substitutedwith alkoxy;

each R^(e) is alkyl;

each R⁶ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OH;

and each R⁷ is independently alkyl, halo, oxo, —C(O)R^(c), or—C(O)OR^(c).

In some embodiments, the compound is not one of the following:

and a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is not one of the following:

and a pharmaceutically acceptable salt thereof.

In some embodiments, each of X, Y, and Z is independently CR′(e.g., CH).

In other embodiments, M is O.

In certain embodiments, M is C(R^(2a))(R^(2b))(e.g., CH₂).

In some embodiments, M is N(R^(2c)) (e.g., NH, NCH₃).

In certain embodiments, A is aryl (e.g., phenyl).

In other embodiments, A is phenyl substituted by 1 R³ (e.g., wherein R³is in the para position).

In some embodiments, A is heteroaryl (e.g., pyridyl).

In other embodiments, A is pyridyl substituted by 1 R³ (e.g., wherein R³is in the para position).

In certain embodiments, R³ is —OR^(c).

In some embodiments, R^(c) is alkyl substituted by one or more R⁶.

In other embodiments, R⁶ is halo (e.g., fluoro).

In certain embodiments, R³ is —OCF₃.

In some embodiments, R¹ is alkyl (e.g., substituted with 1-4 R⁴).

In other embodiments, R⁴ is deuterium, halo, —OR^(c), oxo, carbocyclyl,heteroaryl, —C(O)OR^(c), or —C(O)N(R^(d))₂.

In certain embodiments, R⁴ is deuterium, fluoro, tetrahydrofuranyl,tetrahydropyranyl, pyrimidinyl, OH, C(O)N(CH₃)₂, C(O)N(CH₃)(CH₂CH₃),C(O)N(CH₃)(CH₂CF₃), or C(O)N-tetrahydropyrrolyl.

In some embodiments, R⁴ is halo (e.g., fluoro).

In other embodiments, R¹ is —CH₂CF₃.

In some embodiments, the compound of Formula (I-1) is a compound ofFormula (I-2):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

M is O or C(R2a)(R^(2b))^(;)

R′ is hydrogen, alkyl, —OR^(c), or halogen;

R¹ is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁴;

each of R^(2a) and R^(2b) is independently hydrogen or alkyl, whereinalkyl is optionally substituted by one or more R⁴;

each R^(3a) is independently alkyl, carbocyclyl, heterocyclyl, halo,cyano, nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclylare optionally substituted with one or more R⁵;

each of R⁴ and R⁵ is independently deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R^(d))₂,—C(O)R^(c), —C(O)OR^(c), —S(O)₂—R^(e), —S(O)₂N(R^(d))₂, or —OR^(c),wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted by one or more R⁷;

each R^(c) is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶;

each R^(d) is independently hydrogen or alkyl optionally substitutedwith one or more halogen;

or two R^(d), taken together with the atoms to which they are attached,form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyloptionally substituted with alkoxy;

each R^(e) is alkyl;

each R⁶ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OH;

each R⁷ is independently alkyl, oxo, halo, —C(O)R^(c), or —C(O)OR^(c);and n is 0, 1, 2, 3, or 4.

In some embodiments, the compound is not one of the following:

and a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I-2 is a compound offormula I-3:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula I-2 is a compound offormula I-4:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I-2 is a compound offormula I-5:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I-2 is a compound offormula I-6:

or a pharmaceutically acceptable salt thereof.

In some embodiments of formula I-2, each of X, Y, and Z is CR′, whereinR′ is hydrogen.

In some embodiments of formula I-2, M is O.

In some embodiments of formula I-2, M is C(R^(2a))(R^(2b)).

In some embodiments of formula I-2, R¹ is alkyl, wherein alkyl isoptionally substituted with one or more R⁴.

In some embodiments of formula I-2, each of R⁴ and R⁵ is independentlydeuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,cyano, nitro, —C(O)N(R^(d))₂, —C(O)CH₃, —C(O)OCH₃, —SO₂CH₃,—S(O)₂N(R^(d))₂, or —OR^(c), wherein alkyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is optionally substituted by one or more R⁷.

In some embodiments of formula I-2, each of R⁴ and R⁵ is independentlydeuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,cyano, nitro, —C(O)N(R^(d))₂, —SO₂CH₃, —S(O)₂N(R^(d))₂, or —OR^(c),wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted by one or more R⁷.

In some embodiments of formula I-2, each of R⁴ and R⁵ is independentlydeuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,cyano, nitro, or —OR^(c), wherein alkyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is optionally substituted by one or more R⁷.

In some embodiments of formula I-2, n is 0.

In some embodiments, the compound of Formula (I-1) is a compound ofFormula (I-7):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

M is N(R^(2c));

R′ is hydrogen, alkyl, —OR^(c), or halogen;

R¹ is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁴;

each of R^(2c) is independently hydrogen or alkyl, wherein alkyl isoptionally substituted by one or more R⁴;

each R^(3a) is independently alkyl, carbocyclyl, heterocyclyl, halo,cyano, nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclylare optionally substituted with one or more R⁵;

each of R⁴ and R⁵ is independently deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R^(d))₂,—C(O)R^(c), —C(O)OR^(c), —S(O)₂—R^(e), —S(O)₂N(R^(d))₂, or —OR^(c),wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted by one or more R⁷;

each R^(c) is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶;

each R^(d) is independently hydrogen or alkyl optionally substitutedwith one or more halogen;

or two R^(d), taken together with the atoms to which they are attached,form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyloptionally substituted with alkoxy;

each R^(e) is alkyl;

each R⁶ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OH;

each R⁷ is independently alkyl, oxo, halo, —C(O)R_(c), or —C(O)OR^(c);and n is 0, 1, 2, 3, or 4.

In some embodiments of formula I-7, the compound is not one of thefollowing:

and a pharmaceutically acceptable salt thereof.

In some embodiments of formula I-7, each of X, Y, and Z is CR, whereinR′ is hydrogen.

In some embodiments of formula I-7, R¹ is alkyl, wherein alkyl isoptionally substituted with one or more R⁴.

In some embodiments, R⁴ is halo.

In some embodiments of formula I-7, each of R⁴ and R⁵ is independentlydeuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,cyano, nitro, or —OR^(c), wherein alkyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is optionally substituted by one or more R⁷.

In some embodiments of formula I-7, n is 0.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-a):

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, andZ is independently N or CR′; M is O, C(R^(2a))(R^(2b)), or N(R^(2c)); R′is hydrogen, alkyl, —OR^(c), or halogen (e.g., hydrogen); R¹ ishydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁴; each of R^(2a), R^(2b), and R^(2c) is independently hydrogen oralkyl, wherein alkyl is optionally substituted by one or more R⁴; eachR^(3a) is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵; each of R⁴ and R⁵ isindependently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, halo, cyano, nitro, —C(O)N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c),—S(O)₂—R^(e), —S(O)₂N(R^(d))₂, or —OR^(c), wherein alkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is optionally substituted by one ormore R⁷; each R^(c) is independently hydrogen, alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is optionally substituted by one ormore R⁶; each R^(d) is independently hydrogen or alkyl optionallysubstituted with one or more halogen; or two R^(d), taken together withthe atoms to which they are attached, form a heterocyclyl optionallysubstituted with-OH, alkoxy, or alkyl optionally substituted withalkoxy; each Re is alkyl;

each R⁶ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OH; each R⁷ is independently alkyl, halo, oxo, —C(O)R^(c), or—C(O)OR^(c); and n is 0, 1, 2, 3, or 4.

In some embodiments, X is CR′(e.g., CH). In some embodiments, Y isCR′(e.g., CH). In some embodiments, Z is CR′(e.g., CH). In someembodiments, each of X, Y, and Z is independently CR′(e.g., CH).

In some embodiments, M is Q.

In some embodiments, M is C(R^(2a))(R^(2b)). In some embodiments, M isC(R^(2a))(R^(2b)) and each of R^(2a) and R^(2b) is independentlyhydrogen.

In some embodiments, M is N(R^(2c)). In some embodiments, M is N(R^(2c))and R^(2c) is hydrogen or alkyl (e.g., methyl or ethyl).

In some embodiments, n is 0 or 1. In some embodiments, n is 0. In someembodiments, n is 1.

In some embodiments, R^(3a) is alkyl or —OR^(c). In some embodiments,R^(3a) is alkyl (e.g., ethyl) substituted by one or more R⁵. In someembodiments, R⁵ is —OR^(c). In some embodiments, R^(c) is alkyl (e.g.,methyl). In some embodiments, R^(3a) is —CH₂CH₂OCH₃.

In some embodiments, R^(3a) is —OR^(c). In some embodiments, R^(c) isalkyl. In some embodiments, R^(3a) is —OCH₃.

In some embodiments, R^(3a) is alkyl. In some embodiments, R^(3a) isalkyl substituted with R⁵ (e.g., 1 R⁵). In some embodiments, R⁵ is—OR^(c). In some embodiments, R^(3a) is —CH₂OCH₃.

In some embodiments, R¹ is hydrogen or alkyl. In some embodiments, R¹ ishydrogen.

In some embodiments, R¹ is alkyl. In some embodiments, R¹ is C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, R¹ isunsubstituted C₁₋₆ alkyl (e.g., unsubstituted methyl, unsubstitutedethyl, unsubstituted propyl, or unsubstituted isopropyl). In someembodiments, R¹ is C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, orisopropyl) substituted with 1-4 R⁴. In some embodiments, R¹ is C₁₋₄alkyl substituted with 1-4 R⁴ (e.g., methyl, ethyl, propyl, orisopropyl).

In some embodiments, R⁴ is deuterium, halo, —OR^(c), oxo, carbocyclyl,heteroaryl, —C(O)OR^(c), or —C(O)N(R^(d))₂. In some embodiments, R4 isdeuterium. In some embodiments, R1 is CD₃ or CD₂CD₃.

In some embodiments, R⁴ is halo (e.g., fluoro). In some embodiments, R¹is —CH₂CF₃ or CH₂CHF₂

In some embodiments, R⁴ is —OR^(c) (e.g., —OH or —OCH₃). In someembodiments, le is —CH₂CH₂OCH₃, CH₂CH₂OH, CH₂CH₂CH(OH)CH₃, CH₂CH₂CH₂OH,or CH₂CH₂CH₂OCH₃.

In some embodiments, R⁴ is carbocyclyl (e.g., cyclopropyl). In someembodiments, R¹ is —CH₂CH₂-cyclopropyl or —CH₂-cyclopropyl.

In some embodiments, R⁴ is heterocyclyl (e.g., tetrahydropyranyl,tetrahydrofuranyl). In some embodiments, R¹ is —CH₂— tetrahydropyranylor —CH₂— tetrahydrofuranyl.

In some embodiments, R⁴ is heteroaryl (e.g., oxadiazolyl, pyrimidinyl).In some embodiments, R⁴ is heteroaryl (e.g., oxadiazolyl) substituted by1-4 R⁷. In some embodiments, R¹ is —CH₂CH₂-5-methyl-1,3,4-oxadiazole.

In some embodiments, R⁴ is —C(O)OR^(c) (e.g., —C(O)OH). In someembodiments, R¹ is —CH₂C(O)OH.

In some embodiments, R⁴ is —C(O)N(R^(d))₂ (e.g., C(O)—NH(CH₃)₂,C(O)—NHCH(CH₃)₂, C(O)—NH(CH₃)(CH₂CH₃), C(O)N(CH₃)CH₂CF₃, orC(O)—N-pyrrolidinyl). In some embodiments, R¹ is —CH₂C(O)NHCH(CH₃)₂ or—C(O)—N-pyrrolidinyl.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-b):

or a pharmaceutically acceptable salt thereof, wherein A is aryl orheteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl andheteroaryl are substituted by one or more R³; R¹ is hydrogen, alkyl,carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more R⁴; each R³ isindependently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or—OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl are optionallysubstituted with one or more R⁵; each of R⁴ and R⁵ is independentlydeuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,cyano, nitro, —C(O)N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), —S(O)₂—R^(e),—S(O)₂N(R^(d))₂, or —OR^(c), wherein alkyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is optionally substituted by one or more R⁷; eachR^(c) is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl,or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶; each R⁶ isindependently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or—OH; each R^(d) is independently hydrogen or alkyl optionallysubstituted with one or more halogen; or two R^(d), taken together withthe atoms to which they are attached, form a heterocyclyl optionallysubstituted with —OH, alkoxy, or alkyl optionally substituted withalkoxy; each R^(e) is alkyl; each R⁷ is independently alkyl, halo, oxo,—C(O)R^(c), or —C(O)OR^(c); and n is 0, 1, 2, 3, or 4.

In some embodiments, A is aryl. In some embodiments, A is 6-memberedaryl (e.g., phenyl). In some embodiments, A is phenyl substituted by 1R³. In some embodiments, A is phenyl substituted by 1 R³ in the paraposition.

In some embodiments, A is heteroaryl. In some embodiments, A is6-membered heteroaryl. In some embodiments, A is nitrogen-containingheteroaryl. In some embodiments, A is pyridyl. In some embodiments, A ispyridyl substituted by 1 R³. In some embodiments, A is pyridyl issubstituted by 1 R³ in the para position

In some embodiments, R³ is alkyl or —OR^(c). In some embodiments, R³ is—OR^(c). In some embodiments, R^(c) is alkyl. In some embodiments, R^(c)is alkyl substituted by one or more R⁶. In some embodiments, R⁶ is halo.In some embodiemnts, R³ is —OCH₃, —OCF₃, or —OCH₂CF₃. In someembodiemnts, R³ is —OCF₃.

In some embodiments, R³ is alkyl. In some embodiments, R³ is alkylsubstituted with R⁵ (e.g., 1 R⁵). In some embodiments, R⁵ is —OR^(c). Insome embodiments, R³ is —CH₂OCH₃.

In some embodiments, R¹ is hydrogen or alkyl. In some embodiments, R¹ ishydrogen.

In some embodiments, R¹ is alkyl. In some embodiments, R¹ is C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, R¹ isunsubstituted C₁₋₆ alkyl (e.g., unsubstituted methyl, unsubstitutedethyl, unsubstituted propyl, or unsubstituted isopropyl). In someembodiments, R¹ is C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, orisopropyl) substituted with 1-4 R⁴. In some embodiments, R¹ is C₁₋₄alkyl substituted with 1-4 R⁴ (e.g., methyl, ethyl, propyl, orisopropyl).

In some embodiments, R⁴ is deuterium, halo, —OR^(c), oxo, carbocyclyl,heteroaryl, —C(O)OR^(c), or —C(O)N(R^(d))₂. In some embodiments, R4 isdeuterium. In some embodiments, R¹ is CD₃ or CD₂CD₃.

In some embodiments, R⁴ is halo (e.g., fluoro). In some embodiments, R¹is —CH₂CF₃ or CH₂CHF₂.

In some embodiments, R⁴ is —OR^(c) (e.g., —OH or —OCH₃). In someembodiments, R¹ is —CH₂CH₂OCH₃, CH₂CH₂OH, CH₂CH₂CH(OH)CH₃, CH₂CH₂CH₂OH,or CH₂CH₂CH₂OCH₃.

In some embodiments, R⁴ is carbocyclyl (e.g., cyclopropyl). In someembodiments, R¹ is —CH₂CH₂-cyclopropyl or —CH₂-cyclopropyl.

In some embodiments, R⁴ is heterocyclyl (e.g., tetrahydropyranyl,tetrahydrofuranyl). In some embodiments, R¹ is —CH₂— tetrahydropyranylor —CH₂— tetrahydrofuranyl.

In some embodiments, R⁴ is heteroaryl (e.g., oxadiazolyl, pyrimidinyl).In some embodiments, R⁴ is heteroaryl (e.g., oxadiazolyl) substituted by1-4 R⁷. In some embodiments, R¹ is —CH₂CH₂-5-methyl-1,3,4-oxadiazole.

In some embodiments, R⁴ is —C(O)OR^(c) (e.g., —C(O)OH). In someembodiments, R¹ is —CH₂C(O)OH.

In some embodiments, R⁴ is —C(O)N(R^(d))₂ (e.g., C(O)—NH(CH₃)₂,C(O)—NHCH(CH₃)₂, C(O)—NH(CH₃)(CH₂CH₃), C(O)N(CH₃)CH₂CF₃, orC(O)—N-pyrrolidinyl). In some embodiments, R¹ is —CH₂C(O)NHCH(CH₃)₂ or—C(O)—N-pyrrolidinyl.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-c):

or a pharmaceutically acceptable salt thereof, wherein A is aryl orheteroaryl (e.g., 6-membered aryl or heteroaryl), wherein aryl andheteroaryl are substituted by one or more R³; R¹ is hydrogen, alkyl,carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more R⁴; each R³ isindependently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or—OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl are optionallysubstituted with one or more R⁵; each of R⁴ and R⁵ is independentlydeuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,cyano, nitro, —C(O)N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), —S(O)₂—R^(e),—S(O)₂N(R^(d))₂, or —OR^(c), wherein alkyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is optionally substituted by one or more R⁷; eachR^(c) is independently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl,or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶; each R⁶ isindependently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or—OH; each R^(d) is independently hydrogen or alkyl optionallysubstituted with one or more halogen; or two R^(d), taken together withthe atoms to which they are attached, form a heterocyclyl optionallysubstituted with —OH, alkoxy, or alkyl optionally substituted withalkoxy; each R^(e) is alkyl; each R⁷ is independently alkyl, halo, oxo,—C(O)R^(c), or —C(O)OR^(c); and n is 0, 1, 2, 3, or 4.

In some embodiments, A is aryl. In some embodiments, A is 6-memberedaryl (e.g., phenyl). In some embodiments, A is phenyl substituted by 1R³. In some embodiments, A is phenyl substituted by 1 R³ in the paraposition.

In some embodiments, A is heteroaryl. In some embodiments, A is6-membered heteroaryl. In some embodiments, A is nitrogen-containingheteroaryl. In some embodiments, A is pyridyl. In some embodiments, A ispyridyl substituted by 1 R³. In some embodiments, A is pyridyl issubstituted by 1 R³ in the para position

In some embodiments, R³ is alkyl or —OR^(c). In some embodiments, R³ is—OR^(c). In some embodiments, R^(c) is alkyl. In some embodiments, R^(c)is alkyl substituted by one or more R⁶. In some embodiments, R⁶ is halo.In some embodiemnts, R³ is —OCH₃, —OCF₃, or —OCH₂CF₃. In someembodiemnts, R³ is —OCF₃.

In some embodiments, R³ is alkyl. In some embodiments, R³ is alkylsubstituted with R⁵ (e.g., 1 R⁵). In some embodiments, R⁵ is —OR^(c). Insome embodiments, R³ is —CH₂OCH₃.

In some embodiments, R¹ is hydrogen or alkyl. In some embodiments, R¹ ishydrogen.

In some embodiments, R¹ is alkyl. In some embodiments, R¹ is C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, R¹ isunsubstituted C₁₋₆ alkyl (e.g., unsubstituted methyl, unsubstitutedethyl, unsubstituted propyl, or unsubstituted isopropyl). In someembodiments, R¹ is C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, orisopropyl) substituted with 1-4 R⁴. In some embodiments, R¹ is C₁₋₄alkyl substituted with 1-4 R⁴ (e.g., methyl, ethyl, propyl, orisopropyl).

In some embodiments, R⁴ is deuterium, halo, —OR^(c), oxo, carbocyclyl,heteroaryl, —C(O)OR^(c), or —C(O)N(R^(d))₂. In some embodiments, R4 isdeuterium. In some embodiments, R¹ is CD₃ or CD₂CD₃.

In some embodiments, R⁴ is halo (e.g., fluoro). In some embodiments, R¹is —CH₂CF₃ or CH₂CHF₂.

In some embodiments, R⁴ is —OR^(c) (e.g., —OH or —OCH₃). In someembodiments, R¹ is —CH₂CH₂OCH₃, CH₂CH₂OH, CH₂CH₂CH(OH)CH₃, CH₂CH₂CH₂OH,or CH₂CH₂CH₂OCH₃.

In some embodiments, R⁴ is carbocyclyl (e.g., cyclopropyl). In someembodiments, R¹ is —CH₂CH₂-cyclopropyl or —CH₂-cyclopropyl.

In some embodiments, R⁴ is heterocyclyl (e.g., tetrahydropyranyl,tetrahydrofuranyl). In some embodiments, R¹ is —CH₂— tetrahydropyranylor —CH₂— tetrahydrofuranyl.

In some embodiments, R⁴ is heteroaryl (e.g., oxadiazolyl, pyrimidinyl).In some embodiments, R⁴ is heteroaryl (e.g., oxadiazolyl) substituted by1-4 R⁷. In some embodiments, R¹ is —CH₂CH₂-5-methyl-1,3,4-oxadiazole.

In some embodiments, R⁴ is —C(O)OR^(c) (e.g., —C(O)OH). In someembodiments, R¹ is —CH₂C(O)OH.

In some embodiments, R⁴ is —C(O)N(R^(d))₂ (e.g., C(O)—NH(CH₃)₂,C(O)—NHCH(CH₃)₂, C(O)—NH(CH₃)(CH₂CH₃), C(O)N(CH₃)CH₂CF₃, orC(O)—N-pyrrolidinyl). In some embodiments, R¹ is —CH₂C(O)NHCH(CH₃)₂ or—C(O)—N-pyrrolidinyl.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-d):

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, andZ is independently N or CR′; R′ is hydrogen, alkyl, —OR^(c), or halogen(e.g., hydrogen); R¹ is hydrogen, alkyl, carbocyclyl, or heterocyclyl,wherein alkyl, carbocyclyl, and heterocyclyl are optionally substitutedwith one or more R⁴; each R^(3a) is independently alkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OR^(c), wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁵; each of R⁴ and R⁵ is independently deuterium, alkyl,carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro,—C(O)N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), —S(O)₂—R^(e), —S(O)₂N(R^(d))₂,or —OR^(c); each R^(c) is independently hydrogen, alkyl, carbocyclyl,heterocyclyl, aryl, or heteroaryl, wherein alkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is optionally substituted by one ormore R⁶; each R^(d) is independently hydrogen or alkyl optionallysubstituted with one or more halogen; or two R^(d), taken together withthe atoms to which they are attached, form a heterocyclyl optionallysubstituted with —OH, alkoxy, or alkyl optionally substituted withalkoxy; each R^(e) is alkyl; each R⁶ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and n is 0, 1, 2,3, or 4.

In some embodiments, X is CR′(e.g., CH). In some embodiments, Y isCR′(e.g., CH). In some embodiments, Z is CR′(e.g., CH). In someembodiments, each of X, Y, and Z is independently CR′(e.g., CH).

In some embodiments, n is 0 or 1. In some embodiments, n is 0. In someembodiments, n is 1.

In some embodiments, R^(3a) is alkyl or —OR^(c). In some embodiments,R^(3a) is alkyl (e.g., ethyl) substituted by one or more R⁵. In someembodiments, R⁵ is —OR^(c). In some embodiments, R^(c) is alkyl (e.g.,methyl). In some embodiments, R^(3a) is —CH₂CH₂OCH₃.

In some embodiments, R^(3a) is —OR^(c). In some embodiments, R^(c) isalkyl. In some embodiments, R^(3a) is —OCH₃.

In some embodiments, R^(3a) is alkyl. In some embodiments, R^(3a) isalkyl substituted with R⁵ (e.g., 1 R⁵). In some embodiments, R⁵ is—OR^(c). In some embodiments, R^(3a) is —CH₂OCH₃.

In some embodiments, R¹ is hydrogen or alkyl. In some embodiments, R¹ ishydrogen.

In some embodiments, R¹ is alkyl. In some embodiments, R¹ is C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, or isopropyl). In some embodiments, R¹ isunsubstituted C₁₋₆ alkyl (e.g., unsubstituted methyl, unsubstitutedethyl, unsubstituted propyl, or unsubstituted isopropyl). In someembodiments, R¹ is C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, orisopropyl) substituted with 1-4 R⁴. In some embodiments, R¹ is C₁₋₄alkyl substituted with 1-4 R⁴ (e.g., methyl, ethyl, propyl, orisopropyl).

In some embodiments, R⁴ is deuterium, halo, —OR^(c), oxo, carbocyclyl,heteroaryl, —C(O)OR^(c), or —C(O)N(R^(d))₂. In some embodiments, R4 isdeuterium. In some embodiments, R¹ is CD₃ or CD₂CD₃.

In some embodiments, R⁴ is halo (e.g., fluoro). In some embodiments, R¹is —CH₂CF₃ or CH₂CHF₂.

In some embodiments, R⁴ is —OR^(c) (e.g., —OH or —OCH₃). In someembodiments, R¹ is —CH₂CH₂OCH₃, CH₂CH₂OH, CH₂CH₂CH(OH)CH₃, CH₂CH₂CH₂OH,or CH₂CH₂CH₂OCH₃.

In some embodiments, R⁴ is carbocyclyl (e.g., cyclopropyl). In someembodiments, R¹ is —CH₂CH₂-cyclopropyl or —CH₂-cyclopropyl.

In some embodiments, R⁴ is heterocyclyl (e.g., tetrahydropyranyl,tetrahydrofuranyl). In some embodiments, R¹ is —CH₂— tetrahydropyranylor —CH₂— tetrahydrofuranyl.

In some embodiments, R⁴ is heteroaryl (e.g., oxadiazolyl, pyrimidinyl).In some embodiments, R⁴ is heteroaryl (e.g., oxadiazolyl) substituted by1-4 R⁷. In some embodiments, R¹ is —CH₂CH₂-5-methyl-1,3,4-oxadiazole.

In some embodiments, R⁴ is —C(O)OR^(c) (e.g., —C(O)OH). In someembodiments, R¹ is —CH₂C(O)OH.

In some embodiments, R⁴ is —C(O)N(R^(d))₂ (e.g., C(O)—NH(CH₃)₂,C(O)—NHCH(CH₃)₂, C(O)—NH(CH₃)(CH₂CH₃), C(O)N(CH₃)CH₂CF₃, orC(O)—N-pyrrolidinyl). In some embodiments, R¹ is —CH₂C(O)NHCH(CH₃)₂ or—C(O)—N-pyrrolidinyl.

In any and all aspects, in some embodiments, the compound of Formulae(I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b),(I-c), or (I-d) is selected from:

or a pharmaceutically acceptable salt thereof.

In any and all aspects, in certain embodiments, the compound of Formulae(I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b),(I-c), or (I-d) is selected from:

or a pharmaceutically acceptable salt thereof.

Methods of Treatment

Described herein are compounds and compositions thereof and their use totreat a disease, disorder, or condition relating to aberrant function ofa sodium channel ion channel, e.g., abnormal late sodium (INaL) current.In some embodiments, a compound provided by the present invention iseffective in the treatment of epilepsy or an epilepsy syndrome, aneurodevelopmental disorder, pain, or a neuromuscular disorder.Compounds of the invention may also modulate all sodium ion channels, ormay be specific to only one or a plurality of sodium ion channels, e.g.,Na_(v) 1.1, 1.2, 1.5, 1.6, 1.7, 1.8, and/or 1.9.

In typical embodiments, the present invention is intended to encompassthe compounds disclosed herein, and the pharmaceutically acceptablesalts, pharmaceutically acceptable esters, tautomeric forms, polymorphs,and prodrugs of such compounds. In some embodiments, the presentinvention includes a pharmaceutically acceptable addition salt, apharmaceutically acceptable ester, a hydrate of an addition salt, atautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, astereoisomer or mixture of stereoisomers (pure or as a racemic ornon-racemic mixture) of a compound described herein, e.g. a compound ofFormula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-b),(I-c), or (I-d); such as a compound of Formula (I) named herein.

Epilepsy and Epilepsy Syndromes

The compounds described herein are useful in the treatment of epilepsyand epilepsy syndromes. Epilepsy is a CNS disorder in which nerve cellactivity in the brain becomes disrupted, causing seizures or periods ofunusual behavior, sensations and sometimes loss of consciousness.Seizure symptoms will vary widely, from a simple blank stare for a fewseconds to repeated twitching of their arms or legs during a seizure.

Epilepsy may involve a generalized seizure or a partial or focalseizure. All areas of the brain are involved in a generalized seizure. Aperson experiencing a generalized seizure may cry out or make somesound, stiffen for several seconds to a minute a then have rhythmicmovements of the arms and legs. The eyes are generally open, the personmay appear not to be breathing and actually turn blue. The return toconsciousness is gradual and the person maybe confused from minutes tohours. There are six main types of generalized seizures: tonic-clonic,tonic, clonic, myoclonic, absence, and atonic seizures. In a partial orfocal seizure, only part of the brain is involved, so only part of thebody is affected. Depending on the part of the brain having abnormalelectrical activity, symptoms may vary.

Epilepsy, as described herein, includes a generalized, partial, complexpartial, tonic clonic, clonic, tonic, refractory seizures, statusepilepticus, absence seizures, febrile seizures, or temporal lobeepilepsy.

The compounds described herein may also be useful in the treatment ofepilepsy syndromes. Severe syndromes with diffuse brain dysfunctioncaused, at least partly, by some aspect of epilepsy, are also referredto as epileptic encephalopathies. These are associated with frequentseizures that are resistant to treatment and severe cognitivedysfunction, for instance West syndrome.

In some embodiments, the epilepsy syndrome comprises an epilepticencephalopathy, such as Dravet syndrome, Angelman syndrome, CDKLSdisorder, frontal lobe epilepsy, infantile spasms, West's syndrome,Juvenile Myoclonic Epilepsy, Landau-Kleffner syndrome, Lennox-Gastautsyndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.

In some embodiments, the epilepsy or epilepsy syndrome is a geneticepilepsy or a genetic epilepsy syndrome. In some embodiments, epilepsyor an epilepsy syndrome comprises epileptic encephalopathy, epilepticencephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantileepileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1Amutation, generalized epilepsy with febrile seizures, intractablechildhood epilepsy with generalized tonic-clonic seizures, infantilespasms, benign familial neonatal-infantile seizures, SCN2A epilepticencephalopathy, focal epilepsy with SCN3A mutation, cryptogenicpediatric partial epilepsy with SCN3A mutation, SCN8A epilepticencephalopathy, sudden unexpected death in epilepsy, Rasmussenencephalitis, malignant migrating partial seizures of infancy, autosomaldominant nocturnal frontal lobe epilepsy, sudden expected death inepilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epilepticencephalopathy.

In some embodiments, the methods described herein further compriseidentifying a subject having epilepsy or an epilepsy syndrome (e.g.,epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A,SCN8A mutations, early infantile epileptic encephalopathy, Dravetsyndrome, Dravet syndrome with SCN1A mutation, generalized Epilepsy withfebrile seizures, intractable childhood epilepsy with generalizedtonic-clonic seizures, infantile spasms, benign familialneonatal-infantile seizures, SCN2A epileptic encephalopathy, focalepilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsywith SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpecteddeath in epilepsy, Rasmussen encephalitis, malignant migrating partialseizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy,sudden expected death in epilepsy (SUDEP), KCNQ2 epilepticencephalopathy, or KCNT1 epileptic encephalopathy) prior toadministration of a compound described herein (e.g., a compound ofFormula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a),(I-b), (I-c), or (I-d)).

In one aspect, the present invention features a method of treatingepilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy,epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, earlyinfantile epileptic encephalopathy, Dravet syndrome, Dravet syndromewith SCN1A mutation, generalized Epilepsy with febrile seizures,intractable childhood epilepsy with generalized tonic-clonic seizures,infantile spasms, benign familial neonatal-infantile seizures, SCN2Aepileptic encephalopathy, focal epilepsy with SCN3A mutation,cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8Aepileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussenencephalitis, malignant migrating partial seizures of infancy, autosomaldominant nocturnal frontal lobe epilepsy, sudden expected death inepilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epilepticencephalopathy) comprising administering to a subject in need thereof acompound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, andZ is independently N or CR′; M is O, C(R^(2a))(R^(2b)), or N(R^(2c)); Ais aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), whereinaryl and heteroaryl are substituted by one or more R³; R′ is hydrogen,alkyl, —OR^(c), or halogen; R¹ is hydrogen, alkyl, carbocyclyl, orheterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁴; each of R^(2a), R^(2b), andR^(2c) is independently hydrogen or alkyl, wherein alkyl is optionallysubstituted by one or more R⁴; each R³ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR^(c), whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁵; each of R⁴ and R⁵ is independently deuterium, alkyl,carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro,—OR^(c), —N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), or —C(O)N(R^(d))₂, whereinalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁷; each R^(c) is independently hydrogen,alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁶; each R^(d) is independently hydrogen oralkyl, wherein each alkyl is optionally substituted by one or more R⁶;or two R^(d), taken together with the atoms to which they are attached,form a ring; each R⁶ is independently alkyl, carbocyclyl, heterocyclyl,halo, cyano, nitro, or —OH; and each R⁷ is independently alkyl, halo, oroxo.

A compound of the present invention (e.g., a compound of Formula (I),(I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or(I-d)) may also be used to treat an epileptic encephalopathy, whereinthe subject has a mutation in one or more of ALDH7A1, ALG13, ARHGEF9,ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6,CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1,GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1,KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1,PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B,SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2,SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1,SYNGAP1, SZT2, TBC1D24, and WWOX.

In some embodiments, the methods described herein further compriseidentifying a subject having a mutation in one or more of ALDH7A1,ALG13, ARHGEF9, ARX, ASAH1, CDKLS, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8,CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3,GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2,KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1,PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2,SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22,SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B,STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX prior to administrationof a compound described herein (e.g., a compound of Formula (I), (I-1),(I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a), (I-b), (I-c), or(I-d)).

Neurodevelopmental Disorders

The compounds described herein may be useful in the treatment of aneurodevelopmental disorder. In some embodiments, the neurodevelopmentaldisorder comprises autism, autism with epilepsy, tuberous sclerosis,Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome,22q13.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacialsyndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorderwith epilepsy. In some embodiments, the methods described herein furthercomprise identifying a subject having a neurodevelopmental disorder(e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile Xsyndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome,Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder withepilepsy) prior to administration of a compound described herein (e.g.,a compound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6),(I-7), (I-a), (I-b), (I-c), or (I-d)).

In one aspect, the present invention features a method of treating aneurodevelopmental disorder (e.g., autism, autism with epilepsy,tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelmansyndrome, Dup15q syndrome, 22q13.3 Deletion syndrome, Prader-Willisyndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or aneurodevelopmental disorder with epilepsy) comprising administering to asubject in need thereof a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, andZ is independently N or CR′; M is O, C(R^(2a))(R^(2b)), or N(R^(2c)); Ais aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), whereinaryl and heteroaryl are substituted by one or more R³; R′ is hydrogen,alkyl, —OR^(c), or halogen; R¹ is hydrogen, alkyl, carbocyclyl, orheterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁴; each of R^(2a), R^(2b), andR^(2c) is independently hydrogen or alkyl, wherein alkyl is optionallysubstituted by one or more R⁴; each R³ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR^(c), whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁵; each of R⁴ and R⁵ is independently deuterium, alkyl,carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro,—OR^(c), —N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), or —C(O)N(R^(d))₂, whereinalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁷; each R^(c) is independently hydrogen,alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁶; each R^(d) is independently hydrogen oralkyl, wherein each alkyl is optionally substituted by one or more R⁶;or two R^(d), taken together with the atoms to which they are attached,form a ring; each R⁶ is independently alkyl, carbocyclyl, heterocyclyl,halo, cyano, nitro, or —OH; and each R⁷ is independently alkyl, halo, oroxo.

Pain

The compounds described herein may be useful in the treatment of pain.In some embodiments, the pain comprises neuropathic pain, trigeminalneuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine,familial hemiplegic migraine type 3, cluster headache, trigeminalneuralgia, cerebellar ataxia, or a related headache disorder. In someembodiments, the methods described herein further comprise identifying asubject having pain (e.g., neuropathic pain, trigeminal neuralgia,migraine, hemiplegic migraine, familial hemiplegic migraine, familialhemiplegic migraine type 3, cluster headache, trigeminal neuralgia,cerebellar ataxia, or a related headache disorder) prior toadministration of a compound described herein (e.g., a compound ofFormula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a),(I-b), (I-c), or (I-d)).

In one aspect, the present invention features a method of treating pain(e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegicmigraine, familial hemiplegic migraine, familial hemiplegic migrainetype 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or arelated headache disorder) comprising administering to a subject in needthereof a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, andZ is independently N or CR′; M is O, C(R^(2a))(R^(2b)), or N(R^(2c)); Ais aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), whereinaryl and heteroaryl are substituted by one or more R³; R′ is hydrogen,alkyl, —OR^(c), or halogen; R¹ is hydrogen, alkyl, carbocyclyl, orheterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁴; each of R^(2a), R^(2b), andR^(2c) is independently hydrogen or alkyl, wherein alkyl is optionallysubstituted by one or more R⁴; each R³ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR^(c), whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁵; each of R⁴ and R⁵ is independently deuterium, alkyl,carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro,—OR^(c), —N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), or —C(O)N(R^(d))₂, whereinalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁷; each R^(c) is independently hydrogen,alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁶; each R^(d) is independently hydrogen oralkyl, wherein each alkyl is optionally substituted by one or more R⁶;or two R^(d), taken together with the atoms to which they are attached,form a ring; each R⁶ is independently alkyl, carbocyclyl, heterocyclyl,halo, cyano, nitro, or —OH; and each R⁷ is independently alkyl, halo, oroxo.

Neuromuscular Disorders

The compounds described herein may be useful in the treatment of aneuromuscular disorder. In some embodiments, the neuromuscular disordercomprises amyotrophic lateral sclerosis, multiple sclerosism, myotonia,paramyotonia congenita, potassium-aggravated myotonia, periodicparalysis, hyperkalemic periodic paralysis, hypokalemic periodicparalysis, or laryngospasm with SCN4A mutation. In some embodiments, themethods described herein further comprise identifying a subject having aneuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiplesclerosism, myotonia, paramyotonia congenita, potassium-aggravatedmyotonia, periodic paralysis, hyperkalemic periodic paralysis,hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation)prior to administration of a compound described herein (e.g., a compoundof Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-a),(I-b), (I-c), or (I-d)).

In one aspect, the present invention features a method of treating aneuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiplesclerosism, myotonia, paramyotonia congenita, potassium-aggravatedmyotonia, periodic paralysis, hyperkalemic periodic paralysis,hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation)comprising administering to a subject in need thereof a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, andZ is independently N or CR′; M is O, C(R^(2a))(R^(2b)), or N(R^(2c)); Ais aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), whereinaryl and heteroaryl are substituted by one or more R³; R′ is hydrogen,alkyl, —OR^(c), or halogen; R¹ is hydrogen, alkyl, carbocyclyl, orheterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁴; each of R^(2a), R^(2b), andR^(2c) is independently hydrogen or alkyl, wherein alkyl is optionallysubstituted by one or more R⁴; each R³ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR^(c), whereinalkyl, carbocyclyl, and heterocyclyl are optionally substituted with oneor more R⁵; each of R⁴ and R⁵ is independently deuterium, alkyl,carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro,—OR^(c), —N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), or —C(O)N(R^(d))₂, whereinalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁷; each R^(c) is independently hydrogen,alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁶; each R^(d) is independently hydrogen oralkyl, wherein each alkyl is optionally substituted by one or more R⁶;or two R^(d), taken together with the atoms to which they are attached,form a ring; each R⁶ is independently alkyl, carbocyclyl, heterocyclyl,halo, cyano, nitro, or —OH; and each R⁷ is independently alkyl, halo, oroxo.

Other Disorders

In some embodiments, a compound of the present invention (e.g., acompound of Formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6),(I-7), (I-a), (I-b), (I-c), or (I-d)) may have appropriatepharmacokinetic properties such that they may active with regard to thecentral and/or peripheral nervous system. In some embodiments, thecompounds provided herein are used to treat a cardiovascular diseasesuch as atrial and ventricular arrhythmias, including atrialfibrillation, Prinzmetal's (variant) angina, stable angina, unstableangina, ischemia and reperfusion injury in cardiac, kidney, liver andthe brain, exercise induced angina, pulmonary hypertension, congestiveheart disease including diastolic and systolic heart failure, andmyocardial infarction. In some embodiments, the compounds providedherein may be used in the treatment of diseases affecting theneuromuscular system resulting in itching, seizures, or paralysis, or inthe treatment of diabetes or reduced insulin sensitivity, and diseasestates related to diabetes, such as diabetic peripheral neuropathy.

In one aspect, the present disclosure provides a method of treating aneurological disorder or a psychiatric disorder, wherein the methodcomprises administering to a subject in need thereof a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

M is O, C(R^(2a))(R^(2b)), or N(R^(2c));

A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), whereinaryl and heteroaryl are substituted by one or more R³;

R′ is hydrogen, alkyl, —OR^(c), or halogen;

R¹ is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁴;

each of R^(2a), R^(2b), and R^(2c) is independently hydrogen or alkyl,wherein alkyl is optionally substituted by one or more R⁴;

each R³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵; each of R⁴ and R⁵ isindependently deuterium, alkyl, carbocyclyl, heterocyclyl, aryl,heteroaryl, halo, oxo, cyano, nitro, —OR^(c), —N(R^(d))₂, —C(O)R^(c),—C(O)OR^(c), or —C(O)N(R^(d))₂, wherein alkyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is optionally substituted by one ormore R⁷;

each R^(c) is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶;

each R^(d) is independently hydrogen or alkyl, wherein each alkyl isoptionally substituted by one or more R⁶;

or two R^(d), taken together with the atoms to which they are attached,form a ring;

each R⁶ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OH;

and each R⁷ is independently alkyl, halo, or oxo.

In another aspect, the present disclosure provides a method of treatinga neurological disorder or a psychiatric disorder, wherein the methodcomprises administering to a subject in need thereof a compound ofFormula (I-1):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

M is O, C(R^(2a))(R^(2b)), or N(R^(2c));

A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), whereinaryl and heteroaryl are substituted by one or more R³;

R′ is hydrogen, alkyl, —OR^(c), or halogen;

R¹ is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁴;

each of R^(2a), R^(2b), and R^(2c) is independently hydrogen or alkyl,wherein alkyl is optionally substituted by one or more R⁴;

each R³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵;

each of R⁴ and R⁵ is independently deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, nitro, —OR^(c),—N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), —S(O)₂—R^(e), —S(O)₂N(R^(d))₂, or—C(O)N(R^(d))₂, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁷;

each R^(c) is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl is optionally substituted by one or more R⁶;

each R^(d) is independently hydrogen or alkyl, wherein each alkyl isoptionally substituted by one or more R⁶;

or two R^(d), taken together with the atoms to which they are attached,form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyloptionally substituted with alkoxy;

each R^(e) is alkyl;

each R⁶ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OH;

and each R⁷ is independently alkyl, halo, oxo, —C(O)R^(c), or—C(O)OR^(c).

In some embodiments, the compound is not one of the following:

and a pharmaceutically acceptable salt thereof.

In some embodiments, the neurological disorder is epilepsy.

In some embodiments, the neurological disorder is an epilepticencephalopathy.

In some embodiments, the epileptic encephalopathy comprises Dravetsyndrome, infantile spasms, or Lennox-Gastaut syndrome.

In some embodiments, each of X, Y, and Z is independently CR′(e.g., CH).

In some embodiments, X is N and each of Y and Z is independentlyCR′(e.g., CH).

In some embodiments, Z is N and each of X and Y is independentlyCR′(e.g., CH).

In some embodiments, M is O.

In some embodiments, M is C(R^(2a))(R^(2b)) (e.g., CH₂).

In some embodiments, M is N(R²) (e.g., NH, NCH₃).

In some embodiments, A is aryl (e.g., phenyl).

In some embodiments, A is phenyl substituted by 1 R³ (e.g., wherein R³is in the para position).

In some embodiments, A is heteroaryl (e.g., pyridyl).

In some embodiments, A is pyridyl substituted by 1 R³ (e.g., wherein R³is in the para position).

In some embodiments, R³ is —OR^(c).

In some embodiments, R^(c) is alkyl substituted by one or more R⁶.

In some embodiments, R⁶ is halo (e.g., fluoro).

In some embodiments, R³ is —OCF₃.

In some embodiments, R¹ is alkyl (e.g., substituted with 1-4 R⁴).

In some embodiments, R⁴ is deuterium, halo, —OR^(c), oxo, carbocyclyl,heteroaryl, —C(O)OR^(c), or —C(O)N(R^(d))₂.

In some embodiments, R⁴ is deuterium, fluoro, tetrahydrofuranyl,tetrahydropyranyl, pyrimidinyl, OH, C(O)N(CH₃)₂, C(O)N(CH₃)(CH₂CH₃),C(O)N(CH₃)(CH₂CF₃), or C(O)N— tetrahydropyrrolyl.

In some embodiments, R⁴ is halo (e.g., fluoro).

In some embodiments, R¹ is —CH₂CF₃.

In some embodiments, the compound of Formula (I-1) is a compound ofFormula (I-2):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

M is O or C(R^(2a))(R^(2b));

R′ is hydrogen, alkyl, —OR^(c), or halogen;

R¹ is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁴;

each of R^(2a) and R^(2b) is independently hydrogen or alkyl, whereinalkyl is optionally substituted by one or more R⁴;

each lea R^(3a) is independently alkyl, carbocyclyl, heterocyclyl, halo,cyano, nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclylare optionally substituted with one or more R⁵;

each of R⁴ and R⁵ is independently deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R^(d))₂,—C(O)R^(c), —C(O)OR^(c), —S(O)₂—R^(e), —S(O)₂N(R^(d))₂, or —OR^(c),wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted by one or more R⁷;

each R^(c) is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶;

each R^(d) is independently hydrogen or alkyl optionally substitutedwith one or more halogen;

or two R^(d), taken together with the atoms to which they are attached,form a heterocyclyl optionally substituted with-OH, alkoxy, or alkyloptionally substituted with alkoxy;

each R^(e) is alkyl;

each R⁶ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OH;

each R⁷ is independently alkyl, oxo, halo, —C(O)R^(c), or —C(O)OR^(c); nis 0, 1, 2, 3, or 4.

In some embodiments, the compound of formula I-2 is a compound offormula I-3:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I-2 is a compound offormula I-4:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I-2 is a compound offormula I-5:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula I-2 is a compound offormula I-6:

or a pharmaceutically acceptable salt thereof.

In some embodiments, each of X, Y, and Z is CR′, wherein R′ is hydrogen.

In some embodiments, M is O.

In some embodiments, M is C(R^(2a))(R^(2b)).

In some embodiments, R¹ is alkyl, wherein alkyl is optionallysubstituted with one or more R⁴.

In some embodiments, each of R⁴ and R⁵ is independently deuterium,alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro,or —OR^(c), wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁷.

In some embodiments, n is 0.

In some embodiments, the compound of Formula (I-1) is a compound ofFormula (I-7):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR′;

M is N(R^(2c));

R′ is hydrogen, alkyl, —OR^(c), or halogen;

R¹ is hydrogen, alkyl, carbocyclyl, or heterocyclyl, wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁴;

each of R^(2c) is independently hydrogen or alkyl, wherein alkyl isoptionally substituted by one or more R⁴;

each R^(3a) is independently alkyl, carbocyclyl, heterocyclyl, halo,cyano, nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclylare optionally substituted with one or more R⁵;

each of R⁴ and R⁵ is independently deuterium, alkyl, carbocyclyl,heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —C(O)N(R^(d))₂,—C(O)R^(c), —C(O)OR^(c), —S(O)₂—R^(e), —S(O)₂N(R^(d))₂, or —OR^(c),wherein alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted by one or more R⁷;

each R^(c) is independently hydrogen, alkyl, carbocyclyl, heterocyclyl,aryl, or heteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶;

each R^(d) is independently hydrogen or alkyl optionally substitutedwith one or more halogen;

or two R^(d), taken together with the atoms to which they are attached,form a heterocyclyl optionally substituted with —OH, alkoxy, or alkyloptionally substituted with alkoxy;

each R^(e) is alkyl;

each R⁶ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OH;

each R⁷ is independently alkyl, oxo, halo, —C(O)R^(c), or —C(O)OR^(c);and n is 0, 1, 2, 3, or 4.

In some embodiments, the compound is not one of the following:

and a pharmaceutically acceptable salt thereof.

In some embodiments, each of X, Y, and Z is CR′, wherein R′ is hydrogen.

In some embodiments, R¹ is alkyl, wherein alkyl is optionallysubstituted with one or more R⁴.

In some embodiments, each of R⁴ and R⁵ is independently deuterium,alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro,or —OR^(c), wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁷.

In some embodiments, n is 0.

In one aspect, the present disclosure provides a method comprisesadministering a pharmaceutical composition disclosed herein.

In one aspect, the present disclosure provides a method of treating aneurological disorder or a psychiatric disorder, wherein the methodcomprises administering to a subject in need thereof a compounddisclosed herein, or a pharmaceutically acceptable salt thereof or apharmaceutical composition disclosed herein.

Pharmaceutical Compositions and Routes of Administration

Compounds provided in accordance with the present invention are usuallyadministered in the foi'm of pharmaceutical compositions. This inventiontherefore provides pharmaceutical compositions that contain, as theactive ingredient, one or more of the compounds described, or apharmaceutically acceptable salt or ester thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants. The pharmaceutical compositions may be administered alone orin combination with other therapeutic agents. Such compositions areprepared in a manner well known in the pharmaceutical art (see, e.g.,Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia,Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rdEd. (G. S. Banker & C. T. Rhodes, Eds.)

The pharmaceutical compositions may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

One mode for administration is parenteral, particularly by injection.The forms in which the novel compositions of the present invention maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present invention. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compoundaccording to the present invention in the required amount in theappropriate solvent with various other ingredients as enumerated above,as required, followed by filtered sterilization. Generally, dispersionsare prepared by incorporating the various sterilized active ingredientsinto a sterile vehicle which contains the basic dispersion medium andthe required other ingredients from those enumerated above. In the caseof sterile powders for the preparation of sterile injectable solutions,the preferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral administration is another route for administration of compounds inaccordance with the invention. Administration may be via capsule orenteric coated tablets, or the like. In making the pharmaceuticalcompositions that include at least one compound described herein, theactive ingredient is usually diluted by an excipient and/or enclosedwithin such a carrier that can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe in the form of a solid, semi-solid, or liquid material (as above),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents;

preserving agents such as methyl and propylhydroxy-benzoates; sweeteningagents; and flavoring agents.

The compositions of the invention can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present invention employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thecompounds are generally administered in a pharmaceutically effectiveamount. Preferably, for oral administration, each dosage unit containsfrom 1 mg to 2 g of a compound described herein, and for parenteraladministration, preferably from 0.1 to 700 mg of a compound a compounddescribed herein. It will be understood, however, that the amount of thecompound actually administered usually will be determined by aphysician, in the light of the relevant circumstances, including thecondition to be treated, the chosen route of administration, the actualcompound administered and its relative activity, the age, weight, andresponse of the individual patient, the severity of the patient'ssymptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction, or to protect from the acid conditions of the stomach. Forexample, the tablet or pill can comprise an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate. Compositions for inhalation or insufflation includesolutions and suspensions in pharmaceutically acceptable, aqueous ororganic solvents, or mixtures thereof, and powders. The liquid or solidcompositions may contain suitable pharmaceutically acceptable excipientsas described supra. Preferably, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in preferably pharmaceutically acceptable solvents may benebulized by use of inert gases. Nebulized solutions may be inhaleddirectly from the nebulizing device or the nebulizing device may beattached to a facemask tent, or intermittent positive pressure breathingmachine. Solution, suspension, or powder compositions may beadministered, preferably orally or nasally, from devices that deliverthe formulation in an appropriate manner.

In one aspect, the present disclosure provides a pharmaceuticalcomposition comprising a disclosed compound, or pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

Combination Therapy

A compound or composition described herein (e.g., for use in modulatinga sodium ion channel, e.g., the late sodium (INaL) current) may beadministered in combination with another agent or therapy. A subject tobe administered a compound disclosed herein may have a disease,disorder, or condition, or a symptom thereof, that would benefit fromtreatment with another agent or therapy. These diseases or conditionscan relate to epilepsy or an epilepsy syndrome, a neurodevelopmentaldisorder, pain, or a neuromuscular disorder.

Antiepilepsy Agents

Anti-epilepsy agents include brivaracetam, carbamazepine, clobazam,clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide,ezogabine, felbamate, gabapentin, lacosamide, lamotrigine,levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital,phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate,valproic acid, vigabatrin, zonisamide.

Cardiovascular Agent Combination Therapy

Cardiovascular related diseases or conditions that can benefit from acombination treatment of the sodium channel blockers of the inventionwith other therapeutic agents include, without limitation, anginaincluding stable angina, unstable angina (UA), exercised-induced angina,variant angina, arrhythmias, intermittent claudication, myocardialinfarction including non-STE myocardial infarction (NSTEMI), pulmonaryhypertension including pulmonary arterial hypertension, heart failureincluding congestive (or chronic) heart failure and diastolic heartfailure and heart failure with preserved ejection fraction (diastolicdysfunction), acute heart failure, or recurrent ischemia.

Therapeutic agents suitable for treating cardiovascular related diseasesor conditions include anti-anginals, heart failure agents,antithrombotic agents, antiarrhythmic agents, antihypertensive agents,and lipid lowering agents.

The co-administration of the sodium channel blockers of the inventionwith therapeutic agents suitable for treating cardiovascular relatedconditions allows enhancement in the standard of care therapy thepatient is currently receiving.

Anti-Anginals

Anti-anginals include beta-blockers, calcium channel blockers, andnitrates. Beta blockers reduce the heart's need for oxygen by reducingits workload resulting in a decreased heart rate and less vigorous heartcontraction. Examples of beta-blockers include acebutolol (Sectral),atenolol (Tenormin), betaxolol (Kerlone), bisoprolol/hydrochlorothiazide(Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc),labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL),nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), andtimolol (Blocadren).

Nitrates dilate the arteries and veins thereby increasing coronary bloodflow and decreasing blood pressure. Examples of nitrates includenitroglycerin, nitrate patches, isosorbide dinitrate, andisosorbide-5-mononitrate.

Calcium channel blockers prevent the normal flow of calcium into thecells of the heart and blood vessels causing the blood vessels to relaxthereby increasing the supply of blood and oxygen to the heart. Examplesof calcium channel blockers include amlodipine (Norvasc, Lotrel),bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil),nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine(Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine.

Heart Failure Agents

Agents used to treat heart failure include diuretics, ACE inhibitors,vasodilators, and cardiac glycosides. Diuretics eliminate excess fluidsin the tissues and circulation thereby relieving many of the symptoms ofheart failure. Examples of diuretics include hydrochlorothiazide,metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex),spironolactone (Aldactone), and eplerenone (lnspra).

Angiotensin converting enzyme (ACE) inhibitors reduce the workload onthe heart by expanding the blood vessels and decreasing resistance toblood flow. Examples of ACE inhibitors include benazepril (Lotensin),captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril),lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril(Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril(Mavik).

Vasodilators reduce pressure on the blood vessels by making them relaxand expand. Examples of vasodilators include hydralazine, diazoxide,prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassiumchannel activators, and calcium channel blockers also act asvasodilators.

Cardiac glycosides are compounds that increase the force of the heart'scontractions. These compounds strengthen the pumping capacity of theheart and improve irregular heartbeat activity. Examples of cardiacglycosides include digitalis, digoxin, and digitoxin.

Antithrombotic Agents

Antithrombotics inhibit the clotting ability of the blood. There arethree main types of antithrombotics--platelet inhibitors,anticoagulants, and thrombolytic agents.

Platelet inhibitors inhibit the clotting activity of platelets, therebyreducing clotting in the arteries. Examples of platelet inhibitorsinclude acetylsalicylic acid (aspirin), ticlopidine, clopidogrel(plavix), dipyridamole, cilostazol, persantine sulfinpyrazone,dipyridamole, indomethacin, and glycoprotein IIb/IIIa inhibitors, suchas abciximab, tirofiban, and eptifibatide (Integrelin). Beta blockersand calcium channel blockers also have a platelet-inhibiting effect.

Anticoagulants prevent blood clots from growing larger and prevent theformation of new clots. Examples of anticoagulants include bivalirudin(Angiomax), warfarin (Coumadin), unfractionated heparin, low molecularweight heparin, danaparoid, lepirudin, and argatroban.

Thrombolytic agents act to break down an existing blood clot. Examplesof thrombolytic agents include streptokinase, urokinase, andtenecteplase (TNK), and tissue plasminogen activator (t-PA).

Antiarrhythmic Agents

Antiarrhythmic agents are used to treat disorders of the heart rate andrhythm. Examples of antiarrhythmic agents include amiodarone,dronedarone, quinidine, procainamide, lidocaine, and propafenone.Cardiac glycosides and beta blockers are also used as antiarrhythmicagents.

Combinations with amiodarone and dronedarone are of particular interestgiven the recently discovered synergistic effects of the sodium channelblocker ranolazine and amioarone and dronedarone.

Antihypertensive Agents

Antihypertensive agents are used to treat hypertension, a condition inwhich the blood pressure is consistently higher than normal.Hypertension is associated with many aspects of cardiovascular disease,including congestive heart failure, atherosclerosis, and clot forillation. Examples of antihypertensive agents include alpha-1-adrenergicantagonists, such as prazosin (Minipress), doxazosin mesylate (Cardura),prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide),and terazosin hydrochloride (Hytrin); beta-adrenergic antagonists, suchas propranolol (Inderal), nadolol (Corgard), timolol (Blocadren),metoprolol (Lopressor), and pindolol (Visken); centralalpha-adrenoceptor agonists, such as clonidine hydrochloride (Catapres),clonidine hydrochloride and chlorthalidone (Clorpres, Combipres),guanabenz Acetate (Wytensin), guanfacine hydrochloride (Tenex),methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor),methyldopa and hydrochlorothiazide (Aldoril); combinedalpha/beta-adrenergic antagonists, such as labetalol (Normodyne,Trandate), Carvedilol (Coreg); adrenergic neuron blocking agents, suchas guanethidine (ismelin), reserpine (Serpasil); central nervoussystem-acting antihypertensives, such as clonidine (Catapres),methyldopa (Aldomet), guanabenz (Wytensin); anti-angiotensin II agents;ACE inhibitors, such as perindopril (Aceon) captopril (Capoten),enalapril (Vasotec), lisinopril (Prinivil, Zestril); angiotensin-IIreceptor antagonists, such as Candesartan (Atacand), Eprosartan(Teveten), Irbesartan (Avapro), Losartan (Cozaar), Telmisartan(Micardis), Valsartan (Diovan); calcium channel blockers, such asverapamil (Calan, Isoptin), diltiazem (Cardizem), nifedipine (Adalat,Procardia); diuretics; direct vasodilators, such as nitroprusside(Nipride), diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil(Loniten), verapamil; and potassium channel activators, such asaprikalim, bimakalim, cromakalim, emakalim, nicorandil, and pinacidil.

Lipid Lowering Agents

Lipid lowering agents are used to lower the amounts of cholesterol orfatty sugars present in the blood. Examples of lipid lowering agentsinclude bezafibrate (Bezalip), ciprofibrate (Modalim), and statins, suchas atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor,Altocor), mevastatin, pitavastatin (Livalo, Pitava) pravastatin(Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).

In this invention, the patient presenting with an acute coronary diseaseevent often suffers from secondary medical conditions such as one ormore of a metabolic disorder, a pulmonary disorder, a peripheralvascular disorder, or a gastrointestinal disorder. Such patients canbenefit from treatment of a combination therapy comprising administeringto the patient ranolazine in combination with at least one therapeuticagent.

Pulmonary Disorders Combination Therapy

Pulmonary disorder refers to any disease or condition related to thelungs. Examples of pulmonary disorders include, without limitation,asthma, chronic obstructive pulmonary disease (COPD), bronchitis, andemphysema.

Examples of therapeutics agents used to treat pulmonary disordersinclude bronchodilators including beta2 agonists and anticholinergics,corticosteroids, and electrolyte supplements. Specific examples oftherapeutic agents used to treat pulmonary disorders includeepinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil),salmeterol (Serevent, Serevent Diskus), theophylline, ipratropiumbromide (Atrovent), tiotropium (Spiriva), methylprednisolone(Solu-Medrol, Medrol), magnesium, and potassium.

Metabolic Disorders Combination Therapy

Examples of metabolic disorders include, without limitation, diabetes,including type I and type II diabetes, metabolic syndrome, dyslipidemia,obesity, glucose intolerance, hypertension, elevated serum cholesterol,and elevated triglycerides.

Examples of therapeutic agents used to treat metabolic disorders includeantihypertensive agents and lipid lowering agents, as described in thesection “Cardiovascular Agent Combination Therapy” above. Additionaltherapeutic agents used to treat metabolic disorders include insulin,sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretinmimetics.

Peripheral Vascular Disorders Combination Therapy

Peripheral vascular disorders are disorders related to the blood vessels(arteries and veins) located outside the heart and brain, including, forexample peripheral arterial disease (PAD), a condition that developswhen the arteries that supply blood to the internal organs, arms, andlegs become completely or partially blocked as a result ofatherosclerosis.

Gastrointestinal Disorders Combination Therapy

Gastrointestinal disorders refer to diseases and conditions associatedwith the gastrointestinal tract. Examples of gastrointestinal disordersinclude gastroesophageal reflux disease (GERD), inflammatory boweldisease (IBD), gastroenteritis, gastritis and peptic ulcer disease, andpancreatitis.

Examples of therapeutic agents used to treat gastrointestinal disordersinclude proton pump inhibitors, such as pantoprazole (Protonix),lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec),rabeprazole; H2 blockers, such as cimetidine (Tagamet), ranitidine(Zantac), famotidine (Pepcid), nizatidine (Axid); prostaglandins, suchas misoprostoL (Cytotec); sucralfate; and antacids.

Antibiotics, Analgesics, Antidepressants and Anti-anxiety AgentsCombination Therapy

Patients presenting with an acute coronary disease event may exhibitconditions that benefit from administration of therapeutic agent oragents that are antibiotics, analgesics, antidepressant and anti-anxietyagents in combination with ranolazine.

Antibiotics

Antibiotics are therapeutic agents that kill, or stop the growth of,microorganisms, including both bacteria and fungi. Example of antibioticagents include .beta.-Lactam antibiotics, including penicillins(amoxicillin), cephalosporins, such as cefazolin, cefuroxime, cefadroxil(Duricef), cephalexin (Keflex), cephradine (Velosef), cefaclor (Ceclor),cefuroxime axtel (Ceftin), cefprozil (Cefzil), loracarbef (Lorabid),cefixime (Suprax), cefpodoxime proxetil (Vantin), ceftibuten (Cedax),cefdinir (Omnicef), ceftriaxone (Rocephin), carbapenems, andmonobactams; tetracyclines, such as tetracycline; macrolide antibiotics,such as erythromycin; aminoglycosides, such as gentamicin, tobramycin,amikacin; quinolones such as ciprofloxacin; cyclic peptides, such asvancomycin, streptogramins, polymyxins; lincosamides, such asclindamycin; oxazolidinoes, such as linezolid; and sulfa antibiotics,such as sulfisoxazole.

Analgesics

Analgesics are therapeutic agents that are used to relieve pain.Examples of analgesics include opiates and morphinomimetics, such asfentanyl and morphine; paracetamol; NSAIDs, and COX-2 inhibitors. Giventhe ability of the sodium channel blockers of the invention to treatneuropathic pain via inhibition of the Nay 1.7 and 1.8 sodium channels,combination with analgesics are particularly envisioned. See U.S. PatentApplication Publication 20090203707.

Antidepressant and Anti-anxiety Agents

Antidepressant and anti-anxiety agents include those agents used totreat anxiety disorders, depression, and those used as sedatives andtranquillizers. Examples of antidepressant and anti-anxiety agentsinclude benzodiazepines, such as diazepam, lorazepam, and midazolam;benzodiazepines; barbiturates; glutethimide; chloral hydrate;meprobamate; sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem,Serlift, Stimuloton); escitalopram (Lexapro, Cipralex); fluoxetine(Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan); venlafaxine(Effexor XR, Efexor); citalopram (Celexa, Cipramil, Talohexane);paroxetine (Paxil, Seroxat, Aropax); trazodone (Desyrel); amitriptyline(Elavil); and bupropion (Wellbutrin, Zyban).

Accordingly, one aspect of the invention provides for a compositioncomprising the sodium channel blockers of the invention and at least onetherapeutic agent. In an alternative embodiment, the compositioncomprises the sodium channel blockers of the invention and at least twotherapeutic agents. In further alternative embodiments, the compositioncomprises the sodium channel blockers of the invention and at leastthree therapeutic agents, the sodium channel blockers of the inventionand at least four therapeutic agents, or the sodium channel blockers ofthe invention and at least five therapeutic agents.

The methods of combination therapy include co-administration of a singleformulation containing the sodium channel blockers of the invention andtherapeutic agent or agents, essentially contemporaneous administrationof more than one formulation comprising the sodium channel blocker ofthe invention and therapeutic agent or agents, and consecutiveadministration of a sodium channel blocker of the invention andtherapeutic agent or agents, in any order, wherein preferably there is atime period where the sodium channel blocker of the invention andtherapeutic agent or agents simultaneously exert their therapeuticeffect.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions and methodsprovided herein and are not to be construed in any way as limiting theirscope.

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimal reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include recrystallization,filtration, flash chromatography, trituration, high pressure liquidchromatography (HPLC), or supercritical fluid chromatography (SFC). Notethat flash chromatography may either be performed manually or via anautomated system. The compounds provided herein may be characterized byknown standard procedures, such as nuclear magnetic resonancespectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS).NMR chemical shifts are reported in part per million (ppm) and aregenerated using methods well known to those of skill in the art.

Exemplary general methods for analytical LCMS include Method A (XtimateC18 (2.1 mm×30 mm, 3 μm); A=H₂O (0.04% TFA) and B=CH₃CN (0.02% TFA); 50°C.; 1.2 mL/min; 10-80% B over 0.9 minutes, then 80% B for 0.6 minutes)and Method B (Chromolith Flash RP-18 endcapped C18 (2 mm×25 mm); A=H₂O(0.04% TFA) and B=CH₃CN (0.02% TFA); 50° C.; 1.5 mL/min; 5-95% B over0.7 minutes, then 95% B for 0.4 minutes).

LIST OF ABBREVIATIONS

-   DMF N,N-dimethylformamide-   THF tetrahydrofuran-   MeOH methanol-   CDI 1,1′-Carbonyldiimidazole-   DCM dichloromethane-   EtOH ethanol-   TsOH toluenesulfonic acid-   DMSO dimethyl sulfoxide-   Mel methyl iodide-   EtI ethyl iodide-   TFA trifluoroacetic acid-   TFAA trifluoroacetic anhydride-   LDA lithium diisopropylamide-   DIBAH diisobutylaluminum hydride-   Et₃N trimethylamine-   Pd(dppf)Cl₂ [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)    dichloride-   AcN acetonitrile-   Pd(t-Bu₃P)₂ bis(tri-tent-butylphosphine)palladium(0)-   DIPEA N,N-diisopropylethylamine-   DIEA N,N-diisopropylethylamine-   HATU    1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-   3-oxide hexafluorophosphate-   PPh₃ triphenylphosphine-   DIAD diisopropyl azodicarboxylate-   DEAD diethyl azodicarboxylate-   m-CPBA meta-chloroperoxybenzoic acid-   AcN acetonitrile-   AcOH acetic acid-   BnOH benzyl alcohol-   TDA 4,4′-thiodianiline-   AcCl acetyl chloride-   MSCl methanesulfonyl chloride

Example 1: Synthesis of Compound 1

Synthesis of A-2: To a solution of A-1 (5 g, 26.59 mmol, 1 eq) in THF(50 mL) was added CDI (5.17 g, 31.91 mmol, 1.2 eq), and the mixture wasstirred at 20° C. for 1.5 hours. The mixture was poured into water (50mL), acidized with 1 N HCl (40 mL), extracted with EtOAc (50 mL×2). Thecombined organic phase was washed with sat. Na₂CO₃ (40 mL) and brine (10mL), dried over Na₂SO₄, filtered and concentrated to afford A-2 (6 g,crude) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=7.43-7.00 (m, 3H)

Synthesis of A-3: To a solution of A-2 (3 g, 14.02 mmol, 1 eq), Cs₂CO₃(9.13 g, 28.04 mmol, 2 eq) in DMF (30 mL) was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (4.88 g, 21.03 mmol, 1.5 eq), and the mixturewas stirred at 20° C. for 16 hours. The mixture was diluted with H₂O (30mL) and extracted with EtOAc (50 mL×2). The combined organic phase waswashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product, which was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 25% to 60%) to afford A-3 (1 g, 3.38 mmol)as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=7.34 (dd, 1H), 7.22 (s, 1H),7.14 (d, 1H), 4.40 (q, 2H)

Synthesis of Compound 1: A mixture of A-3 (200 mg, 675.58 μmol, 1 eq),[2-methoxy-4-(trifluoromethoxy)phenyl]boronic acid (191.29 mg, 810.70μmol, 1.2 eq), Pd(t-Bu₃P)₂ (51.79 mg, 101.34 μmol, 0.15 eq) and K₃PO₄(286.81 mg, 1.35 mmol, 2 eq) in dioxane (5 mL) and H₂O (0.3 mL) wasstirred at 85° C. for 16 hours,

The mixture was concentrated to give the crude product, which waspurified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H₂O(0.04% NH₃H₂O) and B=CH₃CN); 55-85% B over 10 minutes) to affordCompound 1 (173.90 mg, 426.48 μmol) as a solid. ¹NMR (DMSO-d₆ 400 MHz)δ_(H)=7.54 (s, 1H), 7.47-7.38 (m, 2H), 7.28 (dd, 1H), 7.13 (s, 1H), 7.06(d, 1H), 4.85 (d, 2H), 3.80 (s, 3H). LCMS R_(t)=1.41 min using Method A,MS ESI calcd. for C₁₇H₁₂F₆NO₄ [M+H]⁺ 408.1, found 407.9.

Example 2: Synthesis of Compound 2

Synthesis of A-4: A mixture of A-2 (500 mg, 2.34 mmol, 1.00 eq),[4-(trifluoromethoxy)phenyl]boronic acid (577.32 mg, 2.80 mmol, 1.20eq), Pd(t-Bu₃P)₂ (238.79 mg, 467.25 μmol, 0.20 eq) and K₃PO₄ (991.82 mg,4.67 mmol, 2.00 eq) in dioxane (8.00 mL) and H₂O (400.00 μL) was stirredat 80° C. for 16 hours. The mixture was then diluted with EtOAc (5 mL),filtered through silica gel, eluted with EtOAc (10 mL) and concentratedto give the crude product that was purified by flash chromatography onsilica gel (PE:EtOAc =5:1 to 1:1) to afford A-4 (350.00 mg, 1.19 mmol)as a solid. ¹NMR (DMSO-d₆ 400 MHz) δ_(H)=11.79 (br s, 1H), 7.76 (d, 2H),7.44 (d, 2H), 7.40-7.36 (m, 2H), 7.34-7.31 (m, 1H).

Synthesis of Compound 2: To a solution of A-4 (50.00 mg, 169.37 μmoll,1.00 eq), Cs₂CO₃ (110.37 mg, 338.74 μmol, 2.00 eq) in DMF (2.00 mL) wasadded 2,2,2-trifluoroethyl trifluoromethanesulfonate (58.97 mg, 254.05μmol, 1.50 eq), and the mixture was stirred at 15° C. for 16 hours. Themixture was then diluted with H₂O (20 mL) and extracted with EtOAc (20mL×2). The combined organic phase was washed with brine (10 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product thatwas purified by Prep-TLC (silica gel, PE:EtOAc=5:1) to afford Compound 2(34.80 mg, 89.83 μmol) as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=7.59-7.54 (m, 2H), 7.39-7.30 (m, 4H), 7.21 (s, 1H), 4.47 (q, 2H).LCMS R_(t)=1.41 min using Method A, MS ESI calcd. for C₁₆H₁₀F₆NO₃ [M+H]⁺378.0, found 377.9.

Example 3: Synthesis of Compound 3

Synthesis of A-5: To a solution of A-2 (3 g, 14.02 mmol, 1 eq) andCs₂CO₃ (9.13 g, 28.04 mmol, 2 eq) in DMF (20 mL) was added ethyl3-bromopropanoate (3.81 g, 21.03 mmol, 1.5 eq), and the mixture wasstirred at 55° C. for 16 hours. The mixture was poured into water (20mL), extracted with EtOAc (50 mL×2). The combined organic phase waswashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product, which was purified by flash chromatography onsilica gel (EtOAc in PE=10% to 20% to 50%) to afford A-5 (1 g, 2.81mmol) as an oil. ¹H NMR (DMSO-d6 400 MHz) δ_(H)=7.66 (s, 1H), 7.30 (s,2H), 4.08-3.99 (m, 4H), 2.78 (t, 2H), 1.12 (t, 3H). LCMS R_(t)=0.80 minusing Method B, MS ESI calcd. for C₁₂H₁₃BrNO₄ [M+H+2]⁺ 316.0, found315.7.

Synthesis of A-6: A mixture of A-5 (800 mg, 2.55 mmol, 1 eq),[4-(trifluoromethoxy)phenyl]boronic acid (629.32 mg, 3.06 mmol, 1.2 eq),K₃PO₄ (1.08 g, 5.09 mmol, 2 eq) and Pd(t-Bu₃P)₂ (195.23 mg, 382.01 μmol,0.15 eq) in dioxane (10 mL) and H₂O (2 mL) was stirred at 85° C. for 16hours. The mixture was concentrated to give the crude product, which waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 20% to30%) to afford A-6 (1 g, 2.53 mmol) as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=7.58 (d, 2H), 7.31 (d, 2H), 7.29-7.26 (m, 3H), 4.19-4.15 (m, 2H),4.14-4.09 (m, 2H), 2.85 (t, 2H), 1.20 (t, 3H).

Synthesis of A-7: A mixture of A-6 (200 mg, 505.91 μmol, 1 eq) andN₂H₄.H₂O (129.21 mg, 2.53 mmol, 125.45 μL, 5 eq) in EtOH (1 mL) wasstirred at 90° C. for 48 hours. The mixture was concentrated to give thecrude A-7 (150 mg, 393.39 μmol) as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=7.80 (d, 2H), 7.54 (d, 2H), 7.51-7.49 (m, 1H), 7.49-7.45 (m, 2H),4.43 (t, 2H), 2.92 (t, 2H).

Synthesis of Compound 3: To a mixture of A-7 (120 mg, 314.71 μmol, 1 eq)in THF (3 mL) was added the 1,1-dimethoxy-N,N-dimethyl-ethanamine (62.87mg, 472.06 μmol, 69.02 μL, 1.5 eq) and the mixture was stirred at 50° C.for 16 hours. The mixture was concentrated to remove EtOH, and theresidue was dissolved in toluene (3 mL), and TsOH.H₂O (54.19 mg, 314.71μmol, 1 eq) was added. The mixture was stirred at 110° C. for 16 hours .The mixture was concentrated, and the residue was purified by Prep-HPLC(Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN);38-68% B over 10 minutes) to afford Compound 3 (42.08 mg, 103.82 μmol)as a solid. ¹H NMR (DMSO-d₆+D₂O 400 MHz) δ_(H)=7.76 (d, 2H), 7.54 (s,1H), 7.45-7.38 (m, 4H), 4.23 (t, 2H), 3.28 (t, 2H), 2.31 (s, 3H). LCMSR_(t)=1.25 min using Method A, MS ESI calcd. for C₁₉H₁₅F₃N₃O₄ [M+H]⁺406.1, found 406.0.

Example 4: Synthesis of Compound 4

Synthesis of A-9: To a solution of A-8 (3 g, 13.27 mmol, 1.00 eq) andCs₂CO₃ (8.65 g, 26.55 mmol, 2.00 eq) in DMF (20 mL) was added2,2,2-trifluoroethyl trifluoromethanesulfonate (4.62 g, 19.91 mmol, 1.5eq), and the mixture was stirred at 15° C. for 16 hours. The mixture wasdiluted with H₂O (20 mL) and extracted with EtOAc (20 mL×2). Thecombined organic phase was washed with brine (10 mL), dried over Na₂SO₄,filtered, and concentrated to give the crude product, which was purifiedby flash chromatography on silica gel (PE:EtOAc=5:1 to 3:1) to affordA-9 (1.2 g, 3.90 mmol) as a solid. ¹NMR (DMSO-d₆ 400 MHz) δ_(H)=7.69 (s,1H), 7.55 (d, 1H), 7.41 (dd, 1H), 4.66 (q, 2H).

Synthesis of A-10: A mixture of A-9 (500 mg, 1.62 mmol, 1 eq) inN₂H₄.H₂O (5 mL) and DMSO (5 mL) was stirred at 130° C. for 20 hours. Themixture was diluted with H₂O (30 mL) and extracted with EtOAc (100mL×2). The combined organic phase was washed with water (30 mL) andbrine (30 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product,which was purified by by flash chromatography on silicagel (EtOAc in PE=10% to 15% to 25%) to afford A-10 (70 mg, 238.04 μmol)as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=7.25 (dd, 1H), 7.15 (d, 1H),7.08 (s, 1H), 4.30 (q, 2H), 3.58 (s, 2H).

Synthesis of Compound 4: A mixture of A-10 (70 mg, 238.04 μmol, 1 eq),[4-(trifluoromethoxy)phenyl]boronic acid (63.72 mg, 309.45 μmol, 1.3eq), Pd(t-Bu₃P)₂ (24.33 mg, 47.61 μmol, 0.2 eq) and K₃PO₄ (101.06 mg,476.08 μmol, 2 eq) in dioxane (5 mL) and H₂O (0.5 mL) was stirred at 80°C. for 12 hours in 20 mL sealed tube under N2. The mixture was dilutedwith H₂O (20 mL) and extracted with EtOAc (50 mL×2). The combinedorganic phase was washed with water (20 mL×2) and brine (20 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product, whichwas purified by Prep-TLC (silica gel, PE:EtOAc=4:1) to afford Compound 4(22.07 mg, 58.56 μmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=7.81(d, 2H), 7.53 (s, 1H), 7.48 (d, 2H), 7.42-7.35 (m, 2H), 4.71 (q, 2H),3.75 (s, 2H). LCMS R_(t)=1.26 min using Method A, MS ESI calcd. forC₁₇H₁₂F₆NO₂ [M+H]⁺ 376.1, found 375.8.

Example 5: Synthesis of Compound 5

A mixture of A-2 (500 mg, 2.34 mmol, 1.00 eq),[4-(trifluoromethoxy)phenyl]boronic acid (577.32 mg, 2.80 mmol, 1.20eq), Pd(t-Bu₃P)₂ (238.79 mg, 467.25 μmol, 0.20 eq) and K₃PO₄ (991.82 mg,4.67 mmol, 2.00 eq) in dioxane (8.00 mL) and H₂O (400.00 μL) was stirredat 80° C. for 16 hours . The mixture was diluted with EtOAc (5 mL),filtered through silica gel, eluted with EtOAc (10 mL) and concentratedto give the crude product, which was purified by flash chromatography onsilica gel (PE:EtOAc=5:1 to 1:1) and Prep-HPLC (Waters Xbridge (150mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN); 38-68% B over 10minutes) to afford Compound 5 (23.72 mg, 78.54 μmol) as a solid. ¹H NMR(DMSO-d₆ 400 MHz) δ_(H)=11.79 (br s, 1H), 7.77 (d, 2H), 7.45 (d, 2H),7.40-7.38 (m, 2H), 7.34-7.32 (m, 1H). LCMS R_(t)=1.14 min using MethodA, MS ESI calcd. for C₁₄H9F₃NO₃ [M+H]⁺ 296.0, found 295.7.

Example 6: Synthesis of Compound 6

A mixture of A-3 (200 mg, 675.58 μmol, 1 eq),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(819.04 mg, 1.35 mmol, 2 eq), Pd(t-Bu₃P)₂ (51.79 mg, 101.34 μmol, 0.15eq) and K₃PO₄ (286.81 mg, 1.35 mmol, 2 eq) in dioxane (10 mL) wasstirred at 80° C. for 16 hours . The mixture was concentrated to givethe crude product, which was purified by Prep-HPLC (Phenomenex Gemini(150 mm×25 mm,10 μm); A=H₂O (0.05% NH₄OH) and B=CH₃CN); 54-84% B over9.5 minutes) and Prep-TLC (silica gel, PE:EtOAc=4:1) to afford Compound6 (104.91 mg, 267.46 μmol) as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=8.32 (d, 1H), 7.82 (dd, 1H), 7.38-7.30 (m, 2H), 7.17 (s, 1H), 6.98(d, 1H), 4.83 (q, 2H), 4.47 (q, 2H). LCMS R_(t)=1.23 min using Method A,MS ESI calcd. for C₁₆H₁₁F₆N₂O₃ [M+H]⁺ 393.1, found 392.8.

Example 7: Synthesis of Compound 7

Synthesis of 7-b: A mixture of2-bromo-1-chloro-4-(trifluoromethoxy)benzene (5.00 g, 18.15 mmol),Pd(dppf)Cl₂.CH₂Cl₂ (1.48 g, 1.82 mmol) and Et₃N (5.51 g, 54.45 mmol) inEtOH (30 mL) was degassed, and refilled with CO. The reaction wasstirred under CO (50 psi) for 16 hours at 80° C., at which point thedesired product was observed by LCMS. The reaction mixture was dilutedwith EtOH (20 mL), and filtered through a Celite pad. The filtrate wasconcentrated. The residue was purified by flash chromatography on silicagel (EtOAc in PE=0%-5%) to afford compound 12-b (2.40 g, 8.93 mmol) asan oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=7.66-7.59 (m, 1H), 7.42 (d, 1H),7.24-7.19 (m, 1H), 4.36 (q, 2H), 1.35 (t, 3H).

Synthesis of 7-c: To a solution of 12-b (2.40 g, 8.93 mmol) in THF (30mL) at −40° C. was added LiA1H₄ (406.67 mg, 10.72 mmol) slowly. Thereaction was stirred at -40° C. for 1 hour. The reaction was quenchedwith sat.NH₄Cl (0.4 mL), diluted with EtOAc (30 mL).

The solid formed was filtered through a Celite pad and eluted with EtOAc(30 mL). The filtrate was concentrated. The residue was purified byflash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) toafford compound 12-c (1.50 g, 6.62 mmol) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=7.45-7.42 (m, 1H), 7.38 (d, 1H), 7.13-7.08 (m, 1H), 4.80(d, 2H), 2.04 (t, 1H).

Synthesis of 7-d: To a solution of compound 12-c (1.50 g, 6.62 mmol) inTHF (20 mL) at 0° C. was added NaH (317.76 mg, 7.94 mmol, 60% purity)slowly. The mixture was stirred at 0° C. for 30 min. Then MeI (2.82 g,19.86 mmol) was added. The reaction was stirred at 20° C. for 16 hoursto give a mixture. The reaction mixture was quenched with sat.NH₄Cl (50mL) and extracted with EtOAc (50 mL×3). The combined organic phase waswashed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by flash chromatography on silica gel (EtOAc inPE=0% to 5% to 10%) to afford compound 12-d (1.40 g, 5.82 mmol) as anoil. ¹H NMR (CDCl₃ 400 MHz) δ_(H)=7.43-7.32 (m, 2H), 7.09 (dd, 1H), 4.54(s, 2H), 3.50 (s, 3H).

Synthesis of 7-e: A mixture of 12-d (400.00 mg, 1.66 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(505.85 mg, 1.99 mmol), KOAc (325.82 mg, 3.32 mmol), X-Phos (197.84 mg,415.00 μmol) and Pd₂(dba)₃ (152.01 mg, 166.00 umol) in dioxane (6 mL)was stirred under N₂ at 80° C. for 16 hours. The mixture was cooled tor.t., concentrated to give the crude product. The crude product waspurified by silica gel column (PE:EA=1:0 to 50:1) to afford compound12-e (300.00 mg, 903.29 μmol) as an oil. LCMS R_(t)=0.99 min usingMethod B, MS ESI calcd. for C₁₅H₂₁BF₃O₄ [M+H]⁺ 333.1, found 332.7.

A mixture of A-3 (100 mg, 0.34 mmol),2-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(134.63mg, 0.41 mmol), K₃PO₄ (110.17mg, 0.52 mmol) and Pd(t-Bu₃P)₂(19.92mg, 0.0400 mmo1) in 1,4-dioxane (2 mL) and water (0.2 mL) wasstirred under N₂ at 85° C. for 16 hours . The mixture was diluted withEtOAc (20 mL), filtered through silica gel and eluted with EtOAc (10mL), and the filtrate was concentrated to give the crude product, whichwas purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10mM NH₄HCO₃) and B=CH₃CN); 53-83% B over 10 minutes) to afford Compound 7(49.97 mg, 0.12 mmol) as a solid. ¹H NMR (DMSO-d6 400 MHz)δ_(H)=7.52-7.46 (m, 3H), 7.41 (s, 2H), 7.21 (dd, 1H), 4.85 (q, 2H), 4.36(s, 2H), 3.25 (s, 3H). LCMS R_(t)=1.40 min using Method A, MS ESI calcd.for C₁₈H₁₄F₆NO₄ [M+H]⁺ 422.0822, found 422.0892.

Example 8: Synthesis of Compound 8

To a solution of Compound 5 (500 mg, 1.69 mmol, 1 eq) in anhydrous DMF(5 mL) was added K₂CO₃ (468.16 mg, 3.39 mmol, 2 eq) and 2-bromoethanol(423.30 mg, 3.39 mmol, 240.51 μL, 2 eq). The resulting mixture wasstirred at 60° C. under N₂ for 16 hours . Saturated NH₄Cl aqueous (10mL) and EtOAc (20 mL) was added to the reaction mixture and the mixturewas stirred for 5 mins. The aqueous phase was extracted with EtOAc (20mL×2) and the combined organic layers were washed with brine (20 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated to affordCompound 8 (250 mg, crude) as an oil. LCMS R_(t)=1.18 min using MethodA, MS ESI calcd. for C₁₆H₁₃F₃NO₄ [M+H]⁺ 340.1, found 339.9.

Example 9: Synthesis of Compound 9

To a solution of Compound 8 (150 mg, 442.13 μmol, 1 eq) in DMF (2 mL)was added NaH (21.22 mg, 530.56 μmol, 60% purity, 1.2 eq) at 0° C., thenMeI (313.78 mg, 2.21 mmol, 137.62 μL,μL, 5 eq) was added to the mixtureat 0° C. The resulting mixture was stirred at 15° C. for 12 hours .Saturated NH₄Cl aqueous (10 mL) and EtOAc (10 mL) were added to thereaction suspension. The resulting mixture was stirred for 5 min. Afterseparation, the organic layer was washed with brine (20 mL×2), driedover anhydrous Na₂SO₄, filtered and concentrated to give the crudeproduct, which was purified by Prep-HPLC (Phenomenex Gemini C18 (150mm×25 mm,10 μm); A=H₂O (0.05% NH₄OH) and B=CH₃CN); 60-70%

B over 8 minutes) to afford Compound 9 (51.05 mg, 144.50 μmol) as asolid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=7.75 (d, 2H), 7.71-7.63 (m, 2H),7.44 (d, 2H), 7.23 (d, 1H), 4.46 (t, 2H), 3.95 (t, 2H), 3.90-3.83 (s,3H). LCMS R_(t)=1.25 min using Method A, MS ESI calcd. for C₁₇H₁₅F₃NO₄[M+H]⁺ 354.1, found 353.9.

Example 10: Synthesis of Compound 10

To a mixture of Compound 5 (150 mg, 508.11 μmol, 1 eq) and Cs₂CO₃(331.10 mg, 1.02 mmol, 2 eq) in DMF (10 mL) was added MeI (360.60 mg,2.54 mmol, 158.16 μL 5 eq) and the mixture was stirred at 50° C. for 16hours . The mixture was diluted with sat.NH₄Cl (50 mL) and extractedwith EtOAc (50 mL×2). The combined organic phase was washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct, which was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm,5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN); 45-75% B over 10 minutes) toafford Compound 10 (49.15 mg, 156.52 μmol) as a solid. ¹H NMR (DMSO-d6+D20 400 MHz) δ_(H)=7.77 (d, 2H), 7.51 (d, 1H), 7.43-7.37 (m, 4H), 3.36(s, 3H). LCMS R_(t)=1.21 min using Method A, MS ESI calcd. forC₁₅H₁₁F₃NO₃ [M+H]⁺ 310.1, found 309.9.

Example 11: Synthesis of Compound 11

To a mixture of Compound 5 (150 mg, 508.11 μmol, 1 eq) and Cs₂CO₃(331.10 mg, 1.02 mmol, 2 eq) in DMF (2 mL) was added the EtI (396.24 mg,2.54 mmol, 203.20 μL, 5 eq) and the mixture was stirred at 50° C. for 16hours . The mixture was diluted with sat.NH₄Cl (50 mL) and extractedwith EtOAc (50 mL×2). The combined organic phase was washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct that was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN); 48-78% B over 10 minutes) toafford Compound 11 (31.14 mg, 96.33 μmol) as a solid. ¹H NMR (DMSO-d₆400 MHz) δ_(H)=7.83 (d, 2H), 7.67 (s, 1H), 7.46 (d, 2H), 7.43 (d, 2H),3.92 (q, 2H), 1.29 (t, 3H). LCMS R_(t)=1.24 min using Method A, MS ESIcalcd. for C₁₆H₁₃F₃NO₃ [M+H]⁺ 324.1, found 323.8.

Example 12: Synthesis of Compound 12

To a mixture of Compound 5 (150 mg, 508.11 μmol, 1 eq) and Cs₂CO₃(331.10 mg, 1.02 mmol, 2 eq) in DMF (2 mL) was addedbromomethylcyclopropane (137.19 mg, 1.02 mmol, 97.30 μL, 2 eq). Themixture was stirred at 60° C. under N₂ for 16 hours . Saturated NH₄Cl(10 mL) and EtOAc (20 mL) were added to the reaction mixture, and theaqueous phase was extracted with EtOAc (20 mL×2). The combined organiclayers were washed with brine (20 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated to give the crude product, which was purifiedby Prep-HPLC (Phenomenex Gemini C18 (150 mm×25 mm,10 μm); A=H₂O (0.04%NH₃H₂O) and B=CH₃CN); 70-80% B over 8 minutes) to afford Compound 12(60.27 mg, 172.54 μmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz)δ_(H)=7.85-7.81 (m, 2H), 7.73 (s, 1H), 7.47 (d, 2H), 7.44 (d, 2H), 3.79(d, 2H), 1.35-1.26 (m, 1H), 0.55-0.48 (m, 2H), 0.46-0.40 (m, 2H). LCMSR_(t)=1.44 min using Method A, MS ESI calcd. for C₁₈H₁₅F₃NO₃ [M+H]⁺350.1, found 349.9.

Example 13: Synthesis of Compound 13

To a mixture of Compound 5 (150 mg, 508.11 μmol, 1 eq) and Cs₂CO₃(331.10 mg, 1.02 mmol, 2 eq) in DMF (2 mL) was added 2-bromopropane(124.99 mg, 1.02 mmol, 95.41 μL, 2 eq). The mixture was stirred at 60°C. under N₂ for 16 hours . Saturated NH₄Cl (10 mL) and EtOAc (20 mL)were added, and the mixture was stirred for 5 min. The aqueous phase wasthen extracted with EtOAc (20 mL×2) and the combined organic layers werewashed with brine (20 mL×2), dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified by Prep-HPLC(Phenomenex Gemini C18 (150 mm×25 mm,10 μm); A=H₂O (0.05% NH₄OH) andB=CH₃CN); 68-78% B over 8 minutes) to afford Compound 13 (48.72 mg,144.44 μmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=7.83 (d, 2H),7.67 (s, 1H), 7.46 (d, 2H), 7.42 (s, 2H), 4.57 (q, 1H), 1.50 (d, 6H).LCMS R_(t)=1.40 min using Method A, MS ESI calcd. for C₁₇H₁₅F₃NO₃ [M+H]⁺338.1, found 337.9.

Example 14: Synthesis of Compound 14

To a mixture of Compound 5 (200 mg, 677.48 μmol, 1 eq) and K2CO₃ (187.26mg, 1.35 mmol, 2 eq) in DMF (5 mL) was added 3-bromopropan-l-ol (188.33mg, 1.35 mmol, 122.29 μL, 2 eq). The reaction mixture was heated to 60°C. and stirred for 16 hours . The mixture was diluted with H₂O (10 mL)and extracted with EtOAc (10 mL×2). The combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated,and the residue was purified by Prep-HPLC (Phenomenex Gemini C18 (150mm×25 mm,10 μm); A=H₂O (0.05% NH₄OH) and B=CH₃CN); 45-75% B over 8minutes) to afford Compound 14 (53.43 mg, 150.93 μmol) as a solid. ¹HNMR (DMSO-d₆ 400 MHz) δ_(H)=7.81 (d, 2H), 7.63 (s, 1H), 7.47 (d, 2H),7.43 (d, 2H), 4.61 (t, 1H), 3.94 (t, 2H), 3.48 (q, 2H), 1.92-1.82 (m,2H). LCMS R_(t)=0.83 min using Method B, MS ESI calcd. for C₁₇H₁₅F₃NO₄[M+H]⁺ 354.1, found 354.1

Example 15: Synthesis of Compound 15

To a mixture of Compound 14 (150 mg, 424.58 μmol, 1 eq) in DMF (15 mL)was added NaH (20.38 mg, 509.49 μmol, 60% purity, 1.2 eq) at 0° C., andthe mixture was stirred for 30 mins. MeI (301.32 mg, 2.12 mmol, 132.16μL, 5 eq) was added, and the mixture was stirred at 15 ° C. for 16 hours. The mixture was diluted with sat. NH₄Cl (40 mL) and extracted withEtOAc (40 mL×2). The combined organic phase was washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct, which was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm,5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN); 35-65% B over 10 minutes)afford Compound 15 (28.92 mg, 78.73 μmol) as a solid. ¹H NMR (DMSO-d₆400 MHz) δ_(H)=7.76 (d, 2H), 7.67-7.62 (m, 2H), 7.43 (d, 2H), 7.21 (d,1H), 4.37-4.31 (m, 2H), 3.85 (s, 3H), 3.53 (t, 2H), 2.14-2.05 (m, 2H).LCMS R_(t)=1.15 min using Method A, MS ESI calcd. for C₁₈H₁₇F₃NO₄ [M+H]⁺368.1, found 367.8

Example 16: Synthesis of Compound 16

Synthesis of A-12: To a mixture of Compound 5 (500 mg, 1.69 mmol, 1 eq)and Cs₂CO₃ (1.10 g, 3.39 mmol, 2 eq) in DMF (15 mL) was added tert-butyl2-bromoacetate (495.54 mg, 2.54 mmol, 375.41 1.5 eq). The reactionmixture was stirred at 55° C. for 16 hours . The mixture was thendiluted with H₂O (30 mL) and extracted with EtOAc (20 mL×2). Thecombined organic phase was washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated, and the residue purified by flashchromatography on silica gel (EtOAc in PE=0% to 10% to 30%) to affordA-12 (500 mg, 1.22 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=7.79(d, 2H), 7.73 (s, 1H), 7.50-7.45 (m, 4H), 4.72 (s, 2H), 1.43 (s, 9H).

Synthesis of Compound 16: A mixture of A-12 (500 mg, 1.22 mmol, 1 eq) inDCM (20 mL) and TFA (10 mL) was stirred at 15° C. for 16 hours . Themixture was concentrated to give the crude product (520 mg), which waspurified by Prep-HPLC (Boston Green ODS (150 mm×30 mm, 5 μm) A=H₂O (0.1%TFA) and B=CH₃CN); 35-65% B over 8minutes) to afford Compound 16 (41.53mg, 0.12 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=13.68-13.15(m, 1H), 7.80 (d, 2H), 7.75 (s, 1H), 7.55-7.38 (m, 4H), 4.70 (s, 2H).LCMS R_(t)=1.22 min using Method A, MSESI calcd.for C₁₆H₉F₃NO₅ [M-H]⁺352.0511, found 352.0569.

Example 17: Synthesis of Compound 17

To the mixture of Compound 16 (100.mg, 0.28 mmol), HATU (161.4 mg, 0.42mmol) and DIEA (73.04mg, 0.57 mmol) in DMF (2 mL) was added pyrrolidine(24.16mg, 0.34 mmol) and the mixture was stirred at 15° C. for 16 hours. The mixture was diluted with sat. NH₄Cl (10 mL), extracted with EtOAc(10 mL×2). The combined organic phase was washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated to give the crude product,which was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm)A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN); 40-70% B over 10 minutes) to affordCompound 17 (19.77 mg, 0.05 mmol) as a solid. ¹H NMR (DMSO-d6+D20 400MHz) δ_(H)=7.73 (d, 2H), 7.48 (s, 1H), 7.44-7.40 (m, 4H), 4.70 (s, 2H),3.52 (t, 2H), 3.28 (t, 2H), 1.97-1.87 (m, 2H), 1.83-1.71 (m, 2H). LCMSR_(t)=1.26 min using Method A, MS ESI calcd. for C₂₀H₁₈F₃N₂O₄ [M+H]⁺407.1, found 407.0.

Example 18: Synthesis of Compound 18

To the mixture of Compound 16 (100 mg, 0.28 mmol), HATU (161.36 mg, 0.42mmol) and DIEA (73.04mg, 0.57 mmol) in DMF (2 mL) was addedpropan-2-amine (20.08mg, 0.34 mmol) and the mixture was stirred at 15°C. for 16 hours . The mixture was diluted with NH₄Cl (10 mL) andextracted with EtOAc (10 mL×2). The combined organic phase was washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product, which was purified by Prep-HPLC (Waters Xbridge (150mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN); 40-70% B over 10minutes), to afford Compound 18 (17.87mg, 0.05 mmol) as a solid. ¹H NMR(DMSO-d₆ 400 MHz) δ_(H)=8.20 (d, 1H), 7.77 (d, 2H), 7.58 (s, 1H),7.50-7.43 (m, 4H), 4.50 (s, 2H), 3.89-3.83 (m, 1H), 1.08 (d, 6H). LCMSR_(t)=1.25 min using Method A, MS ESI calcd. for C₁₉H₁₈F₃N₂O₄ [M+H]⁺395.1, found 395.0.

Example 19: Synthesis of Compound 19

To a mixture of Compound 5 (100 mg, 0.34 mmol), 2-cyclopropylethanol(43.76 mg, 0.51 mmol) and PPh₃ (133.13 mg, 0.51 mmol) in THF (3 mL)under N₂ was added DIAD (102.64 mg, 0.51 mmol) drop-wise at 0° C. Thereaction mixture was then stirred at 15° C. for 16 hours . The reactionmixture was concentrated, and the residue was purified by Prep-HPLC C(Phenomenex Gemini (150 mm×25 mm,10 μm); A=H₂O (0.05% NH₄OH) andB=CH₃CN); 72-82% B over 8 minutes) to afford Compund 19 (57.45 mg, 0.16mmol) as an oil. ¹H NMR (MeOD-d₄ 400 MHz) δ_(H)=7.72 (d, 2H), 7.46 (d,1H), 7.43-7.39 (m, 1H), 7.38-7.32 (m, 3H), 4.03 (t, 2H), 1.71 (q, 2H),0.80-0.68 (m, 1H), 0.46-0.38 (m, 2H), 0.03 (q, 2H). LCMS R_(t)=1.12 minusing Method A, MS ESI calcd. for C₁₉H₁₇F₃NO₃ [M+H]⁺ 364.1, found 364.0.

Example 20: Synthesis of Compound 20

A mixture of A-2 (200 mg, 0.93 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(566.47 mg, 1.87 mmol), Pd(t-BuP₃)₂ (95.51 mg, 0.19 mmol) and K₃PO₄(257.92 mg, 1.87 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) wasstirred at 85° C. for 16 hours . The mixture was diluted with EtOAc (10mL), filtered through silica gel, eluted with EtOAc (10 mL) and thefiltrate concentrated to give the crude product, which was purified byPrep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) andB=CH₃CN); 37-67% B over 10 minutes) to afford Compound 20 (48.55 mg,0.16 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=11.80 (br s, 1H),8.48 (d, 1H), 8.10 (dd, 1H), 7.38 (s, 2H), 7.34 (s, 1H), 7.07 (d, 1H),5.04 (q, 2H). LCMS R_(t)=1.20 min using Method A, MS ESI calcd. forC₁₄H₁₀F₃N₂O₃ [M+H]⁺ 311.1, found 310.8.

Example 21: Synthesis of Compound 21

Synthesis of A-13: A mixture of A-8 (4 g, 17.70 mmol, 1 eq),[4-(trifluoromethoxy)phenyl]boronic acid (4.37 g, 21.24 mmol, 1.2 eq),Pd(t-Bu₃P)₂ (633.09 mg, 1.24 mmol, 0.07 eq) and K₃PO₄ (9.39 g, 44.24mmol, 2.5 eq) in dioxane (200 mL) and H₂O (40 mL) was stirred at 80° C.for 16 hours under N₂. The mixture was then concentrated to a residue,and the residue was diluted with H₂O (100 mL). The mixture was extractedwith EtOAc (200 mL×2), and the combined organic phase was washed withwater (50 mL×2) and brine (50 mL), dried over Na₂SO₄, filtered andconcentrated to give a crude product that was purified by flashchromatography on silica gel (EtOAc in PE=20% to 30% to 50%) to affordA-13 (200 mg, 650.99 μmol). ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=11.18 (br s,1H), 7.85 (d, 2H), 7.61 (d, 1H), 7.51 (d, 2H), 7.37 (dd, 1H), 7.12 (d,1H)

Syntheis of A-14: A mixture of A-13 (200 mg, 650.99 μmol, 1 eq) andCs₂CO₃ (424.21 mg, 1.30 mmol, 2 eq) in CH₃CN (20 mL) was stirred at 20°C. for 0.5 hour. To the mixture was added ethyl 3-bromopropanoate(235.69 mg, 1.30 mmol, 2 eq), then the mixture was stirred at 55° C. for4 hours . The mixture was filtered through Celite, eluted with EtOAc (30mL), and the filtrate was concentrated to give the crude product thatwas purified by flash chromatography on silica gel (EtOAc in PE=10% to20% to 40%) to afford A-14 (130 mg, 319.14 μmol) as an oil. ¹H NMR(CDCl₃, 400 MHz) δ_(H)=7.72-7.63 (m, 3H), 7.37 (d, 2H), 7.31 (dd, 1H),7.22 (d, 1H), 4.13 (q, 2H), 4.10 (t, 2H), 2.80 (t, 2H), 1.22 (t, 3H).

Synthesis of A-15: A mixture of A-14 (120 mg, 294.59 μmol, 1 eq) andhydrazine (944.03 mg, 29.46 mmol, 1.07 mL, 100 eq) in EtOH (3 mL) wasstirred at 100° C. for 14 hours . After cooling, the mixture wasconcentrated to afford A-15 (110 mg, 259.82 μmol) as a solid. LCMSR_(t)=0.76 min using Method B, MS ESI calcd. for C₁₈H₁₇F₃N₃O₃ [M+H]⁺380.1, found 379.9

Synthesis of Compound 21: To a mixture of A-15 (110 mg, 289.98 μmol, 1eq) in THF (4 mL) was added 1,1-dimethoxy-N,N-dimethyl-ethanamine (77.24mg, 579.97 μmol, 84.79 μL, 2 eq), then the mixture was stirred at 55° C.for 4 hours. The mixture was concentrated to a residue, followed byaddition of toluene (4 mL) and TsOH.H₂O (11.03 mg, 58.00 μmol, 0.2 eq).The mixture was stirred at 110° C. for 16 hours . After cooling, themixture was diluted with H₂O (10 mL), and the mixture was extracted withEtOAc (30 mL×2). The combined organic phase was washed with water (10mL×2) and brine (10 mL), dried over Na₂SO₄, filtered and concentrated togive a crude product that was purified by Prep-TLC (silica gel,PE:EtOAc=1:1) to afford Compound 21 (50.22 mg, 124.51 μmol) as a solid.¹H NMR (CDCl₃ 400 MHz) δ_(H)=7.57 (d, 2H), 7.36-7.28 (m, 3H), 7.22 (dd,1H), 6.92 (s, 1H), 4.20 (t, 2H), 3.58 (s, 2H), 3.24 (t, 2H), 2.41 (s,3H). LCMS R_(t)=1.17 min using Method A, MS ESI calcd. for C₂oH₁₇F₃N₃O₃[M+H]⁺ 404.1, found 403.9

Example 22: Synthesis of Compound 22

Synthesis of A-18: A mixture of A-17 (2 g, 10.58 mmol, 1 eq) and CDI(2.06 g, 12.70 mmol, 1.2 eq) in THF (30 mL) was stirred at 50° C. for 2hours . The mixture was then filtered through silica gel, and thefiltrate was concentrated to provide the crude product A-18 (2.3 g,crude). ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=12.82-11.26 (m, 1H), 8.04 (d,1H), 7.71 (d, 1H).

Synthesis of A-19: To a solution of A-18 (2.5 g, 11.63 mmol, 1 eq) andCs₂CO₃ (7.58 g, 23.26 mmol, 2 eq) in DMF (20 mL) was added2,2,2-trifluoroethyl trifluoromethanesulfonate (5.40 g, 23.26 mmol, 2eq), and the mixture was stirred at 20° C. for 16 hours. The mixture wasdiluted with H₂O (10 mL) and extracted with EtOAc (40 mL×2). Thecombined organic phase was washed with brine (15 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product, which was purifiedby flash chromatography on silica gel (EtOAc in PE=20% to 40% to 60%) toafford A-19 (700 mg, 2.36 mmol) as a solid. ¹H NMR (DMSO-d₆400 MHz)δ_(H)=8.16 (d, 1H), 8.13 (d, 1H), 4.90-4.82 (m, 2H).

Synthesis of Compound 22: A mixture of A-19 (200 mg, 673.34 μmol, 1 eq),[4-(trifluoromethoxy)phenyl]boronic acid (207.99 mg, 1.01 mmol, 1.5eq), Pd(t-Bu₃P)₂ (51.62 mg, 101.00 μmol, 0.15 eq) and K₃PO₄ (285.86 mg,1.35 mmol, 2 eq) in dioxane (6 mL) and H₂O (0.6 mL) was stirred at 90°C. for 16 hours . The mixture was concentrated and the crude product waspurified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H₂O(0.05% NH₄OH) and B=CH₃CN); 63-73% B over 8 minutes) to afford Compound22 (35.08 mg, 90.81 μmol) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.29(d., 1H), 7.60-7.54 (m, 2H), 7.47 (d, 1H), 7.37 (d, 2H), 4.50 (q, 2H).LCMS R_(t)=1.33 min using Method A, MS ESI calcd. for C₁₅H₉F₆N₂O₃ [M+H]⁺379.0, found 378.9.

Example 23: Synthesis of Compound 23

Synthesis of A-21: A mixture of A-20 (5000 mg, 22.73 mmol),2,2,2-trifluoroethanamine hydrochloride (4620 mg, 34.09 mmol) and DIEA(8811.82 mg, 68.18 mmol) in THF (30 mL) was stirred at 70° C. for 16hours. After cooling to room temperature, the mixture was concentrated,then the mixture was diluted with H₂O (100 mL) and extracted with EtOAc(100 mL×2). The combined organic phase was washed with brine (100 mL),dried over Na₂SO₄, filtered and concentrated to give the crude productthat was purified by flash chromatography on silica gel (EtOAc in PE=0to 30% to 100%) to give the product A-21 (6100 mg, 20.40 mmol). ¹H NMR(CDCl₃, 400 MHz) δ_(H)=8.28 (br s, 1H), 8.09 (dd, 1H), 7.12 (s, 1H),6.94 (dd, 1H), 4.08-3.86 (m, 2H)

Synthesis of A-22: A mixture of A-21 (2 g, 6.69 mmol), Fe (3.74 g, 66.88mmol) and NH₄Cl (3.58 g, 66.88 mmol) in ethanol (20 mL) and water (20mL) was stirred at 75° C. for 2 hours . After cooling to r.t, themixture was filtrated through Celite, and eluted with EtOAc (50 mL×2).The filtration was concentrated and diluted with EtOAc (50 mL), washedwith (30 mL×2) and brine (30 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product of A-22 (1.7 g, 6.32 mmol). LCMSR_(t)=0.74 min using Method B, MS ESI calcd. for C₈H₉BrF₃N₂ [M+H]⁺269.0, found 268.9.

Synthesis of A-23: A mixture of A-22 (1000 mg, 3.72 mmol) and CDI(523.68 mg, 3.72 mmol) in THF (10 mL) was stirred at 20° C. for 16 hours. After cooling to r.t, the mixture was concentrated to give a residuethat was purified by flash chromatography on silica gel (EtOAc in PE=0%to 50% to 100%) to afford A-23 (930 mg, 2.97 mmol) as a solid. ¹H NMR(CDCl3, 400 MHz) δ_(H)=9.76 (br s, 1H), 7.30-7.26 (m, 1H), 7.23 (s, 1H),7.02 (d, 1H), 4.46 (q, 2H).

Synthesis of Compound 23: A mixture of A-23 (400 mg, 1.36 mmol),[4-(trifluoromethoxy)phenyl]boronic acid (558.34 mg, 2.71 mmol),Pd(dppf)Cl₂.CH₂Cl₂ (221.42 mg, 0.27 mmol) and K₂CO₃ (374.73 mg, 2.71mmol) in 1,4-dioxane (15 mL) and water (3 mL) was stirred at 90° C. for16 hours . The mixture was concentrated to give a residue that waspurified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H₂O(0.05% NH₄OH) and B=CH₃CN); 50-80% B over 10 minutes)to afford Compound23 (44.78 mg, 0.12 mmol) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.80(br s, 1H), 7.58 (d, 2H), 7.36-7.28 (m, 3H), 7.25-7.16 (m, 2H), 4.53 (q,2H). LCMS R_(t)=1.19 min using Method A, MS ESI calcd. for C₁₆H₁₁F₆N₂O₂[M+H]⁺ 377.1, found 377.0.

Example 24: Synthesis of Compound 24

Synthesis of A-24: To the mixture of the A-4 (1500 mg, 5.08 mmol) andK₂CO₃ (1402.39 mg, 10.16 mmol) in MeCN (5 mL) was added tert-butyl3-bromopropanoate (1062.36 mg, 5.08 mmol), and the mixture was stirredat 50° C. for 16 hours . The mixture was cooled to r.t., diluted withsat.NH₄Cl (50 mL), extracted with EtOAc (50 mL×2), and the combinedphase was washed over brine (20 mL), dried over Na₂SO₄ and concentratedto give the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=5% to 10% to 20%) to affordA-24 (1300 mg, 3.07 mmol) as an oil. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=7.83(d, 2H), 7.72 (s, 1H), 7.47 (d, 2H), 7.43 (s, 2H), 4.10 (t, 2H), 2.75(t, 2H), 1.31 (s, 9H).

Synthesis of Compound 24: A mixture of A-24 (700 mg, 1.65 mmol) in TFA(5 mL, 1.65 mmol) and DCM (10 mL) was stirred at 15° C. for 16 hours .The mixture was concentrated, diluted with H₂O (20 mL) and extractedwith DCM (20 mL). The combined organic phase was washed with brine (10mL), dried over Na₂SO₄, filtered and concentrated to give a residue thatwas purified by Prep-HPLC (Phenomenex Synergi (150 mm×30 mm, 4 μm);A=H₂O (0.1% TFA) and B=CH₃CN); 45-75% B over 8 minutes) to affordCompound 24 (34.06 mg, 0.09 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz)δ_(H)=12.46 (br s, 1H), 7.82 (d, 2H), 7.72 (s, 1H), 7.47 (d, 2H), 7.43(s, 2H), 4.09 (t, 2H), 2.76 (t, 2H). LCMS R_(t)=1.24 min using Method A,ESI calcd. for C₁₇H₁₃F₃NO₅ [M+H]⁺ 368.0668, found 368.0683

Example 25: Synthesis of Compound 25

To the mixture of Compound 24 (150 mg, 0.41 mmol), HATU (232.79 mg, 0.61mmol) and DIEA (105.37 mg, 0.82 mmol) in DMF (2 mL) was addedN-methylmethanamine (22.09 mg, 0.49 mmol), and the mixture was stirredat 15° C. for 16 hours . The mixture was diluted with sat.NH₄Cl (10 mL),extracted with EtOAc (10 mL×2). The combined organic phase was washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givea residue that was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm,5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN); 40-70% B over 10 minutes) toafford Compound 25 (77.68 mg, 0.20 mmol) as a solid. ¹H NMR (DMSO-d₆ 400MHz) δ_(H)=7.83 (d, 2H), 7.73 (s, 1H), 7.47 (d, 2H), 7.44-7.39 (m, 2H),4.07 (t, 2H), 2.92 (s, 3H), 2.83 (t, 2H), 2.80 (s, 3H). LCMS R_(t)=1.166min using Method A, MS ESI calcd. for C₁₉H₁₈F₃N₂O₄ [M+H]⁺ 395.1, found395.0.

Example 26: Synthesis of Compound 26

To the mixture of Compound 24 (150 mg, 0.4100 mmol), HATU (232.79 mg,0.61 mmol) and DIEA (105.37 mg, 0.82 mmol) in DMF (2 mL) was addedpyrrolidine (34.86 mg, 0.49 mmol) and the mixture was stirred at 15° C.for 16 hours . The mixture was diluted with sat.NH₄Cl (10 mL) andextracted with EtOAc (10 mL×2). The combined organic phase was washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givea residue that was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm,5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN); 43-73% B over 10 minutes) toafford Compound 26 (72.24 mg,0.17 mmol) as an oil. ¹H NMR (DMSO-d₆+D₂O400 MHz) δ_(H)=7.77 (d, 2H), 7.58 (s, 1H), 7.46-7.33 (m, 4H), 4.07 (t,2H), 3.30 (t, 2H), 3.17 (t, 2H), 2.73 (t, 2H), 1.82-1.73 (m, 2H),1.71-1.62 (m, 2H). LCMS R_(t)=1.20 min ung Method A, MS ESI calcd. forC₂₁H₂₀F₃N₂O₄ [M+H]⁺ 421.1, found 421.0.

Example 27: Synthesis of Compound 27

To a mixture of Compound 24 (150 mg, 0.41 mmol), HATU (232.94 mg, 0.61mmol) and DIEA (105.53 mg, 0.82 mmol) in DMF (3 mL) was addedpropan-2-amine (28.97 mg, 0.49 mmol). The resulting mixture was stirredat 15° C. for 16 hours . To the stirred mixture was added saturatedNH₄Cl aqueous (15 mL) and EtOAc (15 mL), and the organic layer waswashed with brine (15 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated to give a crude product. The crude product was purified byPrep-HPLC (Xtimate C18 (250 mm×50 mm, 10 μm) A=H₂O (0.05% NH₄OH) andB=CH₃CN); 50-80% B over 8 minutes) to afford Compound 27 (78.39 mg, 0.19mmol) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=7.62-7.56 (m, 2H), 7.36(d, 1H), 7.33-7.27 (m, 3H), 7.26-7.23 (m, 1H), 5.43 (d, 1H), 4.21 (t,2H), 4.04-3.93 (m, 1H), 2.66 (t, 2H), 1.01 (d, 6H). LCMS R_(t)=1.30 minsusing Method A, MS ESI calcd. for C₂₀H₂₀F₃N₂O₄ [M+H]⁺ 409.1, found 409.0

Example 28: Synthesis of Compound 28

To a solution of Compound 24 (150 mg, 0.41 mmol), HATU (232.94 mg, 0.61mmol) and

DIEA (105.53 mg, 0.82 mmol) in DMF (3 mL) was added N-ethylethanamine(35.85 mg, 0.49 mmol). The resulting mixture was stirred at 15° C. for16 hours . To the stirring mixture was added saturated NH₄Cl aqueous (15mL) and EtOAc (15 mL). The organic layer was washed with brine (15 mL),dried over anhydrous Na₂SO₄, filtered and concentrated to give a crudeproduct that was purified by Prep-HPLC Xtimate C18 (250 mm×50 mm, 10 μm)A=H₂O (0.05% NH₄OH) and B=CH₃CN); 58-88% B over 8 minutes) to affordCompound 28 (88.41 mg, 0.213 mmol) as an oil. ¹H NMR (DMSO-d₆ 400 MHz)δ_(H)=7.82 (d, 2H), 7.73 (s, 1H), 7.47 (d, 2H), 7.42 (s, 2H), 4.10 (t,2H), 3.29-3.21 (m, 4H), 2.82 (t, 2H), 1.05 (t, 3H), 0.96 (t, 3H). LCMSR_(t)=1.35 mins using Method A, MS ESI calcd. for C₂₁H₂₂F₃N₂O₄ [M+H]⁺423.1, found 423.0.

Example 29: Synthesis of Compound 29

Synthesis of A-26: To a solution of A-25 (10 g, 71.38 mmol) in methanol(200 mL) was added CH₃ONa (3.85 g, 71.38 mmol) slowly at 15° C. Theresulting solution was stirred at 15° C. for 30 min. Then Br₂ (11.41 g,71.38 mmol) was added to the solution dropwise 0° C. and the mixture wasstirred at 15° C. for 16 hours . The reaction solution was quenched withglacial AcOH (1.25 mL) and concentrated to give the crude product ofA-26 (22.00 g, crude) as a solid. The crude product was used in the nextstep without further purification. LCMS R_(t)=0.54 mins using Method B,MS ESI calcd. for C₅H₄BrN₂O₃ [M+H]⁺218.9, found 219.1.

Synthesis of A-27: To a mixture of A-26 (10 g, 45.66 mmol) and K₂CO₃(6.31 g, 45.66 mmol) in DMF (150 mL) was added bromomethylbenzene (3.9g, 22.83 mmol). The resulting mixture was stirred at 60° C. for 16 hours. The reaction mixture was cooled to room temperature. Water (300 mL)and EtOAc (200 mL) was added to the reaction mixture. The organic layerwas washed with brine (100 mL×2), dried over Na₂SO₄, filtered andconcentrated to give a crude product that was purified by flashchromatography on silica gel (PE:EtOAc=PE to 10:1 to 5:1 to 3:1) toafford A-27 (2.95 g, 9.54 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz)δ_(H)=8.05 (s, 2H), 7.44-7.34 (m, 5H), 5.39 (s, 2H).

Synthesis of A-28: A mixture of A-27 (950 mg, 3.07 mmol),[4-(trifluoromethoxy)phenyl]boronic acid (759.45 mg, 3.69 mmol),Pd(t-Bu₃P)₂ (235.61 mg, 0.46 mmol) and K₃PO₄ (1304.9 mg, 6.15 mmol) in1,4-dioxane (8 mL) and water (0.8 mL) was stirred under N₂ at 85° C. for16 hours . The reaction mixture was cooled to room temperature andfiltered through Celite. The filtrate was concentrated to give a crudeproduct that was purified by flash chromatography on silica gel(PE:EtOAc=10:1 to 5:1 to 3:1) to afford A-28 (960 mg, 2.46 mmol) as asolid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.39 (d, 1H), 8.20-8.11 (m, 3H),7.54-7.33 (m, 7H), 5.44 (s, 2H).

Synthesis of A-29: A mixture of A-28 (150 mg, 0.38 mmol) and Pd/C (50mg) in methanol (15 mL) was stirred under H₂ at 15° C. for 16 hours .The reaction mixture was filtered through Celite and the filtrate wasconcentrated to afford A-29 (100 mg, 0.37 mmol) as a solid. ¹H NMR(DMSO-d₆ 400 MHz) δ_(H)=7.98 (d, 2H), 7.34 (d, 2H), 7.00 (d, 1H), 6.90(d, 1H), 5.58 (s, 2H).

Synthesis of Compound 29: A mixture of2-amino-6-[4-(trifluoromethoxy)phenyl]-pyridin-3-ol (100 mg, 0.37 mmol)and CDI (62.57 mg, 0.44 mmol) in THF (5 mL) was stirred at 60° C. for 16hours . The reaction mixture was cooled to room temperature andconcentrated to give a crude product that purified by Prep-HPLC XtimateC18 (250 mm×50 mm, 10 μm) A=H₂O (0.05% NH₄OH) and B=CH₃CN); 30-60% Bover 8 minutes) to afford Compound 29 (50.89 mg, 0.17 mmol) as a solid.¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=12.55 (br s, 1H), 8.11 (d, 2H), 7.76-7.69(m, 2H), 7.47 (br d, 2H). LCMS=R_(t)=1.23 min using Method A, MS ESIcalcd. for C₁₃H₈F₃N₂O₃ [M+H]⁺ 297.0, found 296.9.

Example 30: Synthesis of Compound 30

Synthesis of A-30: To a solution of Compound 14 (320 mg, 0.91 mmol) inDCM (10 mL) at 0° C. was added methanesulfonyl chloride (0.08 mL, 1.09mmol). The reaction mixture was stirred at 15° C. for 1 hour to give asolution The reaction was quenched with sat.NH₄Cl (30 mL), extractedwith DCM (20 mL×3). The combined organic phase was washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated to give A-30 (420 mg,crude) as a solid. ¹H NMR MeOD-d₄ 400 MHz) δ_(H)=7.75 (d, 2H), 7.49 (d,1H), 7.44-7.40 (m, 1H), 7.38-7.30 (m, 3H), 4.34 (t, 2H), 4.08 (t, 2H),3.05 (s, 3H), 2.31-2.22 (m, 2H).

Synthesis of Compound 30: To the mixture of pyrrolidin-2-one (59.18 mg,0.70 mmol) in DMF (3 mL) was added NaH (27.82mg, 0.70 mmol) at 0° C. andthe mixture was stirred for 30 mins. Then A-30 (200.mg, 0.46 mmol) wasadded, and the mixture was stirred at 15° C. for 16 hours . The mixturewas quenched by sat.NH₄Cl (10 mL) and extracted with EtOAc (10 mL×2).The combined organic phase was washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated to give the crude product, which waspurified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mMNH₄HCO₃) and B=CH₃CN); 40-70% B over 10 minutes) to afford Compound 30(12.42mg, 0.03 mmol) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=7.59 (d,2H), 7.34-7.28 (m, 4H), 7.16 (s, 1H), 3.89 (t, 2H), 3.47-3.39 (m, 4H),2.38 (t, 2H), 2.13-1.99 (m, 4H). LCMS R_(t)=1.16 min using Method A, MSESI calcd. for C₂₁H₂₀F₃N₂O₄ [M+H]⁺ 421.1, found 421.0.

Example 31: Synthesis of Compound 31

To the mixture of oxazolidin-2-one (60.56 mg, 0.70 mmol) in DMF (3 mL)was added the NaH (27.82 mg, 0.70 mmol) at 0° C. and the mixture wasstirred for 30 mins. Then A-30 (200 mg, 0.46 mmol) was added and themixture was stirred at 15° C. for 16 hours . The mixture was quenched bysat.NH₄Cl (10 mL), extracted with EtOAc (10 mL×2), and the combinedorganic phase was washed with brine (10 mL), dried over Na₂SO₄, filteredand concentrated to give a crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=10% to 20%) to affordCompound 31 (36.59 mg, 0.0843 mmol) as a solid. ¹H NMR (DMSO-d₆, 400MHz) δ_(H)=7.83 (d, 2H), 7.71 (s, 1H), 7.48 (d, 2H), 7.44 (d, 2H),4.29-4.16 (m, 2H), 3.91 (t, 2H), 3.61-3.49 (m, 2H), 3.26 (t, 2H),2.06-1.91 (m, 2H). LCMS R_(t)=1.15 min using Method A, MS ESI calcd. forC₂₀H₁₈F₃N₂O₅ [M+H]⁺ 423.1, found 423.0.

Example 32: Synthesis of Compound 32

To a mixture of t-BuOK (47.71 mg, 0.43 mmol) and Compound 23 (80.00 mg,0.21 mmol) in THF (10 mL) was added CH₃I (150.86 mg, 1.06 mmol). Themixture was stirred at 20° C. for 16 hours . After cooling to r.t, themixture was concentrated to give the crude product, which was purifiedby Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H₂O (0.05%NH₄OH) and B=CH₃CN); 68-78% B over 8 minutes) afford Compound 32 (20.18mg, 0.05 mmol) as a solid. ¹H NMR (CDCl₃ 400 MHz) δ_(H)=7.58 (d, 2H),7.36 (dd, 1H), 7.31 (d, 2H), 7.23 (s, 1H), 7.09 (d, 1H), 4.53 (q, 2H),3.49 (s, 3H). LCMS R_(t)=1.23 min using Method A, ESI calcd. forC₁₇H₁₃F₆N₂O₂ [M+H]⁺ 391.0876, found 391.0818.

Example 33: Synthesis of Compound 33

Synthesis of A-31: To a solution of A-28 (660 mg, 1.69 mmol) in Methanol(5 mL) was added NiCl₂.6H₂O (1025.74 mg, 5.07 mmol). To the resultingmixture was added NaBH₄ (319.59 mg, 8.45 mmol) slowly and the mixturewas stirred at 15° C. for 1 hour to give a suspension . Saturated NaHCO₃aqueous (10 mL) and DCM (20 mL) was added to the reaction mixture andfiltered through Celite. The filtrate was separated, and the organiclayer was washed with brine (10 mL×2), dried over anhydrous Na₂SO₄,filtered through silica gel (300-400 mesh) and concentrated to give A-31(220 mg, 0.61 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.02 (d,2H), 7.52 (d, 2H), 7.43-7.30 (m, 5H), 7.21-7.16 (m, 1H), 7.12-7.07 (m,1H), 5.87 (s, 2H), 5.19 (s, 2H). LCMS R_(t)=0.768 mins in 1.5 minschromatography, MS ESI calcd. for C₁₉H₁₆F₃N₂O₂ [M+H]⁺ 361.1, found361.0.

Synthesis of A-32: To a solution of A-31 (200 mg, 0.56 mmol) in THF (10mL) was added TEA (168.51 mg, 1.67 mmol) and TFAA (233.15 mg, 1.11 mmol)slowly. The resulting mixture was stirred at 15° C. for 16 hours to givea solution . Saturated NaHCO₃ aqueous (10 mL) and EtOAc (20 mL) wasadded to the reaction mixture. After separation, the organic layer waswashed with brine (10 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated to give A-32 (180 mg, 0.37 mmol) as a solid. LCMSR_(t)=0.97 min using Method B, MS ESI calcd. for C₂₁H₁₅F₆N₂O₃ [M+H]⁺457.1, found 456.9.

Synthesis of A-33: To a solution of A-32 (180 mg, 0.39 mmol) in DMF (5mL) was added NaH (78.89 mg, 1.97 mmol). The resulting mixture wasstirred at 15° C. for 10 mins. To the mixture was added1,1,1-trifluoro-2-(trifluoromethylsulfonyl)ethane (255.72 mg, 1.18mmol). The reaction mixture was stirred at 15° C. for 16 hours .Saturated NH₄Cl aqueous (25 mL) and EtOAc (30 mL) were added to thereaction mixture. After separation, the organic layer was washed withbrine (20 mL×2), dried over anhydrous Na₂SO₄, filtered and concentratedto give a crude product that was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 10% to 20%) to afford A-33 (100 mg, 0.22mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.08 (d, 2H), 7.53 (d,2H), 7.44-7.38 (m, 4H), 7.37-7.32 (m, 1H), 7.30-7.20 (m, 2H), 6.74 (t,1H), 5.23 (s, 2H), 4.34-4.20 (m, 2H). LCMS R_(t)=1.03 min using MethodB, MS ESI calcd. for C₂₁H₁₇F₆N₂O₂ [M+H]⁺ 443.1, found 443.4.

Synthesis of A-34: To a solution of A-33 (100 mg, 0.23 mmol) in methanol(5 mL) was added Pd/C (50 mg, 0.2300 mmol). The resulting mixture wasstirred at 15° C. under H₂ balloon (15 psi) for 3 hours to give asuspension . The reaction mixture was filtered through Celite, and thefiltrate was concentrated to give A-34 (86 mg, 0.22 mmol) as a solid. ¹HNMR (DMSO-d₆ 400 MHz) δ_(H)=8.03 (d, 2H), 7.37 (d, 2H), 7.12 (d, 1H),6.97 (d, 1H), 6.51 (t, 1H), 4.29-4.19 (m, 2H). LCMS R_(t)=0.89 min usingMethod B, MS ESI calcd. for C₁₄H₁₁F₆N₂O₂ [M+H]⁺353.1, found 353.3.

Synthesis of Compound 33: To a solution of A-34 (86 mg, 0.24 mmol) inTHF (4 mL) was added CDI (41.28 mg, 0.29 mmol) and the resulting mixturewas stirred at 55° C. under N₂ for 16 hours to give a colorless solution. The reaction solution was cooled to room temperature and concentratedto give a crude product that was purified by Prep-HPLC (Waters Xbridge(150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO3) and B=CH₃CN); 45-75% B over10 minutes) to afford Compound 33 (35.88 mg, 0.09 mmol) as a solid. ¹HNMR (DMSO-d₆ 400 MHz) δ_(H)=8.20 (d, 2H), 7.94-7.85 (m, 2H), 7.50 (d,2H), 4.79 (q, 2H). LCMS R_(t)=1.41 min using Method A, MS ESI calcd. forC₁₃H9F6N203 [M+H]⁺ 379.0, found 378.9.

Example 34. Synthesis of Compound 34

Synthesis of A-35: To a solution of A-18 (300 mg, 1.4 mmol) in DMF (7mL) was added Cs₂CO₃ (909.77 mg, 2.79 mmol) and BnBr (286.38 mg, 1.67mmol), and the mixture was stirred at 20° C. for 2 hours . The mixturewas poured into water (15 mL) and extracted with EtOAc (30 mL×2). Thecombined organic phase was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product that was purified byflash chromatography on silica gel (EtOAc in PE=20% to 40% to 60%) toafford A-35 (370 mg, 0.93 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz)δ_(H)=8.12 (d, 1H), 7.96 (d, 1H), 7.45-7.40 (m, 2H), 7.40-7.31 (m, 3H),5.04 (s, 2H). LCMS R_(t)=0.81 min using Method B, MS ESI calcd. forC₁₃H₁₀BrN₂O₂ [M+H+2]⁺307.0, found 306.7.

Synthesis of Compound 34: A mixture of A-35 (300 mg, 0.98 mmol),[4-(trifluoromethoxy)phenyl]boronic acid (242.96 mg, 1.18 mmol),Pd(t-Bu₃P)₂ (100.48 mg, 0.20 mmol) and K₃PO₄ (416.87 mg, 1.97 mmol) in1,4-dioxane (10 mL) and water (2 mL) was stirred at 90° C. for 16 hours. After cooling to r.t., the mixture was concentrated to give the crudeproduct, which was purified by by flash chromatography on silica gel(EtOAc in PE=15% to 40% to 70%) and Prep-HPLC (Waters Xbridge (150 mm×25mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN); 57-87% B over 8 minutes)to afford Compound 34 (43.43 mg, 0.11 mmol) as a solid. ¹H NMR (DMSO-d₆400 MHz) δ_(H)=8.32 (d, 1H), 8.03 (d, 1H), 7.81 (d, 2H), 7.52-7.45 (m,4H), 7.40-7.29 (m, 3H), 5.12 (s, 2H). LCMS Rt=1.40 min using Method A,MS ESI calcd. for C₂₀H₁₄F₃N₂O₃ [M+H]⁺ 387.1, found 387.0

Example 35. Synthesis of Compound 35

To a mixture of A-4 (100 mg, 0.34 mmol), 2-pyrimidin-2-ylethanol (75.69mg, 0.61 mmol) and PPh₃ (159.75 mg, 0.61 mmol) in THF (3 mL) under N₂was added DEAD (106.19 mg, 0.61 mmol) drop-wise at 0° C. The reactionmixture was then stirred at 20° C. for 16 hours. The mixture wasconcentrated to give the crude product that was purified by Prep-HPLC(Phenomenex Gemini (150 mm×25 mm,10 μm); A=H₂O (0.05% NH₄OH) andB=CH₃CN); 60-70% B over 8 minutes) to afford Compound 35 (65.01 mg,0.1575 mmol) as an oil. ¹H NMR (DMSO-d6+D20 400 MHz) δ_(H)=8.69 (d, 2H),7.77 (d, 2H), 7.52 (s, 1H), 7.46 (d, 2H), 7.40 (d, 2H), 7.33 (t, 1H),4.33 (t, 2H), 3.33 (t, 2H). LCMS R_(t)=1.26 min in using Method A, MSESI calcd. for C₂₀H₁₅F₃N₃O₃ [M+H]⁺ 402.1, found 402.0.

Example 36. Synthesis of Compound 36

Synthesis of A-37: To a mixture of A-36 (5 g, 38.6 mmol) and K2CO₃(10.65 g, 77.2 mmol) in DMF (40 mL) was added bromomethylbenzene (5.04mL, 42.46 mmol). The reaction mixture was heated to 60° C. and stirredfor 16 hours . After cooling, the mixture was diluted with H₂O (150 mL),and the mixture was extracted with EtOAc (100 mL×2). The combinedorganic phase was washed with brine (80 mL), dried over Na₂SO₄, filteredand concentrated to afford A-37 (8000 mg, 36.42 mmol), which was useddirectly in next step. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.14 (d, 1H),7.44-7.34 (m, 5H), 7.26-7.21 (m, 2H), 5.11 (s, 2H).

Synthesis of A-38: A mixture of A-37 (3 g, 13.66 mmol),[4-(trifluoromethoxy)phenyl]-boronic acid (3.09 g, 15.02 mmol),Pd(t-Bu₃P)₂ (1.0 g, 2.05 mmol) and K₃PO₄ (5.79 g, 27.31 mmol) in1,4-dioxane (15 mL) and water (1.5 mL) under N₂ was heated to 90° C. andstirred for 16 hours . After cooling, the reaction mixture was dilutedwith EtOAc (20 mL), filtered through a Celite pad, eluted with EtOAc (20mL) and concentrated. The residue was purified by flash chromatographyon silica gel (EtOAc in PE=0% to 10% to 20%) to afford A-38 (4000 mg,11.58 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.46 (d, 1H),8.13 (d, 2H), 7.96 (d, 1H), 7.57 (dd, 1H), 7.52-7.32 (m, 7H), 5.25 (s,2H).

Synthesis of A-39: To a solution of A-38 (4 g, 11.58 mmol) in DCM (100mL) was added m-CPBA (4.69 g, 23.17 mmol). The reaction mixture wasstirred at 15° C. for 16 hours. The reaction was quenched withsat.NaHCO₃ (200 mL), extracted with DCM (150 mL×3). The combined organicphase was washed with sat.NaHCO₃ (100 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 20% to 40%) to afford A-39 (2000 mg, 5.54mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.27 (d, 1H), 7.92 (d,2H), 7.61 (d, 1H), 7.49-7.36 (m, 7H), 7.21 (dd, 1H), 5.24 (s, 2H).

Synthesis of A-40: To a mixture of A-39 (2 g, 5.54 mmol) in AcOH (20 mL)at 0° C. was added fuming HNO3 (20 mL) dropwise. The reaction mixturewas then heated to 90° C. and stirred for 16 hours . The reactionmixture was concentrated, and the residue was treated with sat.NaHCO₃(100 mL) and extracted with EtOAc (100 mL×2). The combined organic phasewas washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography on silicagel (EtOAc in PE=0% to 30% to 50%) to afford A-40 (250 mg, 0.55 mmol) asa solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.76 (s, 1H), 8.43-8.31 (m, 3H),7.94 (d, 2H), 7.77 (d, 2H), 7.52 (d, 2H), 5.60 (s, 2H).

Synthesis of A-41: A mixture of A-40 (200 mg, 0.44 mmol) and wet Pd/C(200 mg) in methanol (10 mL) was degassed and refilled with Hz. Thereaction mixture was stirred under H₂ (50 psi) at 20° C. for 16 hours .The reaction mixture was diluted with MeOH (10 mL), filtered through aCelite pad and eluted with MeOH (10 mL). The filtrate was concentratedto give A-41 (160 mg, crude). LCMS R_(t)=0.67 min using Method B, MS ESIcalcd. for C₁₂H₁₀F₃N₂O₂ [M+H]⁺ 271.1, found 270.9.

Synthesis of Compound 36: To a solution of A-41 (160 mg, 0.59 mmol) inTHF (5 mL) was added CDI (143.89 mg, 0.89 mmol). The reaction mixturewas heated to 60° C. and stirred for 2 hours . The reaction mixture wasconcentrated, and the residue was purified by Prep-HPLC (PhenomenexGemini (150 mm×25 mm,10 μm); A=H₂O (0.05% NH₄OH) and B=CH₃CN); 25-55% Bover 8 minutes) to afford Compound 36 (25.54 mg, 0.09 mmol) as a solid.¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=12.35 (br s, 1H), 8.56 (s, 1H), 8.17 (d,2H), 7.72 (s, 1H), 7.46 (d, 2H). LCMS R_(t)=1.05 min using Method A, MSESI calcd. for C₁₃H₈F₃N₂O₃ [M+H]⁺ 297.0, found 296.9.

Example 37. Synthesis of Compound 37

Synthesis of A-43: To a solution of A-42 (2 g, 8.42 mmol) in Toluene (20mL) was added phenylmethanol (1 g, 9.27 mmol),tris[2-(2-methoxyethoxy)ethyl]amine (272.43 mg, 0.84 mmol), KOH (471.7mg, 8.42 mmol) and K₂CO₃ (1162.4 mg, 8.42 mmol), and the mixture wasstirred at for 4 hours. The mixture was filtered through Celite andeluted with EtOAc (30 mL×3). The filtrate was concentrated to give thecrude product that was filtered through silica gel (˜20 g), The filtratewas concentrated to give the impure product, which was triturated fromi-Pr₂O (10 mL) to afford A-43 (2200 mg, 7.12 mmol) as a solid. ¹H NMR(CDCl₃, 400 MHz) δ_(H)=8.45 (d, 1H), 8.41 (d, 1H), 7.49 (d, 2H),7.44-7.30 (m, 3H), 5.58 (s, 2H).

Synthesis of A-44: A mixture of A-43 (1 g, 3.23 mmol),[4-(trifluoromethoxy)phenyl]-boronic acid (1 g, 4.85 mmol), K₂CO₃(892.86 mg, 6.47 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (396.25 mg, 0.49 mmol) in1,4-dioxane (10 mL) and water (1 mL) was stirred at 90° C. for 16 hours.After cooling to r.t., the mixture was diluted with PE (10 mL), filteredthrough silica gel (˜20 g) and eluted. The filtrate was concentrated togive the crude product that was purified by flash chromatography onsilica gel (EtOAc in PE=10% to 15% to 20%) to afford A-44 (900 mg, 2.30mmol) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.60 (d, 1H), 8.47 (d,1H), 7.59 (d, 2H), 7.54 (d, 2H), 7.45-7.32 (m, 5H), 5.65 (s, 2H).

Synthesis of A-45: A mixture of A-44 (400 mg, 1.02 mmol) and Pd/C (100mg) in Methanol (10 mL) was stirred at 20° C. under H2 balloon (15 psi)for 2 hours . The mixture was filtered through Celite and eluted withMeOH (10 mL×2). The filtrate was concentrated to give the crude productA-45 (250 mg, 0.93 mmol) as a solid, which was used directly without anyfurther purification. LCMS R_(t)=0.73 min using Method B, MS ESI calcd.for C₁₂H₁₀F₃N₂O₂ [M+H]⁺271.0, found 270.9.

Synthesis of Compound 37: A mixture of A-45 (300 mg, 1.11 mmol) and CDI(360.05 mg, 2.22 mmol) in THF (10 mL) was stirred at 60° C. for 16 hours. The mixture was filtered through silica gel and concentrated, and theresidue was dissolved in MeOH (˜3 mL). The filtrate was concentrated toafford Compound 37 (47.80 mg, 0.16 mmol) as a solid. ¹H NMR (DMSO-d₆ 400MHz) δ_(H)=8.26 (d, 1H), 7.84 (d, 2H), 7.75 (d, 1H), 7.49 (d, 2H). LCMSR_(t)=1.08 min using Method A, MS ESI calcd. for C₁₃H₈F₃N₂O₃ [M+H]⁺297.0, found 296.9.

Example 38. Synthesis of Compound 38

To a solution of Compound 16 (80 mg, 0.23 mmol) in DMF (3 mL) was addedHATU (155 mg, 0.41 mmol), DIPEA (87.81 mg, 0.68 mmol) andN-methylmethanamine hydrochloride (22.16 mg, 0.27 mmol). The resultingmixture was stirred at 15° C. for 16 hours . Saturated NH₄Cl aqueous (20mL) and EtOAc (20 mL) were added to the reaction solution. Afterseparation, the organic layer was washed with brine (20 mL×2), driedover anhydrous Na₂SO₄, filtered and concentrated to give a residue thatwas purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10mM NH₄HCO₃) and B=CH₃CN); 37-67% B over 10 minutes) to afford Compound38 (26.69 mg, 0.07 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=7.77(d, 2H), 7.61 (s, 1H), 7.49-7.44 (m, 4H), 4.85 (s, 2H), 3.10 (s, 3H),2.86 (s, 3H). LCMS R_(t)=1.18 min using Method A, MS ESI calcd. forC₁₈H16F₃N₂O₄ [M+H]⁺ 381.1, found 381.0.

Example 39. Synthesis of Compound 39

To a mixture of Compound 16 (90 mg, 0.25 mmol), HATU (145.31 mg, 0.38mmol) and DIPEA (65.85 mg, 0.51 mmol) in DMF (2 mL) was added theN-ethylethanamine (33.79 mg, 0.31 mmol) and the mixture was stirred at15° C. for 16 hours . The mixture was diluted with sat.NH₄Cl (10 mL),extracted with EtOAc (10 mL×2). The combined organic phase was washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated to aresidue that was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN); 45-75% B over 10 minutes) toafford Compound 39 (41.81 mg, 0.1024 mmol) as a solid. ¹H NMR(DMSO-d₆+D₂O 400 MHz) δ_(H)=7.73 (d, 2H), 7.48-7.39 (m, 5H), 4.79 (s,2H), 3.39 (q, 2H), 3.26 (q, 2H), 1.20 (t, 3H), 1.00 (t, 3H). LCMSR_(t)=1.25 min using Method A, MS ESI calcd. for C₂₀H₂₀F₃N₂O₄ [M+H]⁺409.1, found 409.0.

Example 40. Synthesis of Compound 40

To a solution of Compound 16 (80 mg, 0.23 mmol) in DMF (3 mL) was addedHATU (155 mg, 0.41 mmol), DIPEA (87.81 mg, 0.68 mmol) and morpholine(23.68 mg, 0.27 mmol). The resulting mixture was stirred at 15° C. for16 hours . Saturated NH₄Cl aqueous (20 mL) and EtOAc (20 mL) were addedto the reaction solution. After separation, the organic layer was washedwith brine (20 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product that was purified by Prep-HPLC(Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN);37-67% B over 10 minutes) to afford Compound 40 (8.33 mg, 0.02 mmol) asa solid. ¹H NMR (DMSO-d6 400 MHz) δ_(H)=7.76 (d, 2H), 7.60 (d, 1H),7.51-7.41 (m, 4H), 4.91 (s, 2H), 3.72-3.66 (m, 2H), 3.60-3.54 (m, 4H),3.47-3.41 (m, 2H). LCMS R_(t)=1.17 min using Method A, MS ESI calcd. forC₂₀H₁₈F₃N₂O₅ [M+H]⁺ 423.1, found 423.0.

Example 41. Synthesis of Compound 41

To a mixture of Compound 16 (90 mg, 0.25 mmol), HATU (145.31 mg, 0.38mmol) and DIPEA (65.85 mg, 0.51 mmol) in DMF (2 mL) was addedmethanamine hydrochloride (20.64 mg, 0.31 mmol), and the mixture wasstirred at 15° C. for 16 hours . The mixture was diluted with sat.NH₄Cl(10 mL), extracted with EtOAc (10 mL×2). The combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedto give a residue that purified by Prep-HPLC (Waters Xbridge (150 mm×25mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN); 8-38% B over 9 minutes) toafford Compound 41 (27.35 mg, 0.0747 mmol) as a solid. ¹H NMR (CDCl3,400 MHz) δ_(H)=7.56 (d, 2H), 7.37-7.29 (m, 4H), 7.22 (d, 1H), 5.97 (brs, 1H), 4.50 (s, 2H), 2.87 (d, 3H). LCMS R_(t)=1.14 min using Method A,MS ESI calcd. for C₁₇H₁₄F₃N₂O₄ [M+H]⁺ 367.1, found 367.0.

Example 42. Synthesis of Compound 42

To a solution of Compound 16 (80 mg, 0.23 mmol) in DMF (3 mL) was addedHATU (155 mg, 0.41 mmol), DIPEA (146.34 mg, 1.13 mmol) and ammoniahydrochloride (60.57 mg, 1.13 mmol). The resulting mixture was stirredat 15° C. for 16 hours. Saturated NH₄Cl aqueous (20 mL) and EtOAc (20mL) were added to the reaction solution. After separation, the organiclayer was washed with brine (20 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10mM NH₄HCO₃) and B=CH₃CN); 34-54% B over 10 minutes) to afford Compound42 (22.9 mg, 0.07 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz)δ_(H)=7.85-7.75 (m, 3H), 7.61 (s, 1H), 7.50-7.43 (m, 4H), 7.36 (s, 1H),4.52 (s, 2H). LCMS R_(t)=1.11 min using Method A, MS ESI calcd. forC₁₆H₁₂F₃N₂O₄ [M+H]⁺ 353.1, found 352.9.

Example 43. Synthesis of Compound 43

Synthesis of A-46: To a mixture of A-18 (300 mg, 1.4 mmol) and Cs₂CO₃(681.91 mg, 2.09 mmol) in DMF (5 mL) was added CH₃I (0.13 mL, 2.09mmol). The mixture was stirred at 20° C. for 16 hours. The reaction wasdiluted with water (20 mL), and the mixture was extracted with EtOAc (20mL×2). The combined organic phase was washed with brine (10 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product, whichwas purified by flash chromatography on silica gel (EtOAc in PE=0% to30% to 100%) to afford A-46 (110 mg, 0.33 mmol) as a solid. ¹H NMR(CDCl₃ 400 MHz) δ_(H)=8.12 (d, 1H), 7.38 (d, 1H), 3.43 (s, 3H). LCMSR_(t)=0.63 min using Method B, MS ESI calcd. for C₇H₆BrN₂O₂ [M+H]⁺229.0, found 228.8.

Synthesis of Compound 43: A mixture of A-46 (110 mg, 0.48 mmol),[4-(trifluoromethoxy)phenyl]boronic acid (118.69 mg, 0.58 mmol),Pd(t-Bu₃P)₂ (49.09 mg, 0.10 mmol) and K₃PO₄ (203.93 mg, 0.96 mmol) in1,4-dioxane (3 mL) and water (0.5 mL) was stirred at 80° C. for 16 hoursunder N₂. The mixture was filtered through silica gel and eluted withEtOAc (20 mL×2). The filtrate was concentrated and diluted with EtOAc(30 mL), washed with water (10 mL×2) and brine (10 mL), dried overNa₂SO₄, filtered and concentrated to give the crude product that waspurified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm, 10 μm); A=H₂O(0.05% NH₄OH) and B=CH₃CN); 55-66% B over 8 minutes) to afford Compound43 (17.91 mg, 0.06 mmol) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.22(d, 1H), 7.58 (d, 2H), 7.40-7.30 (m, 3H), 3.50 (s, 3H). LCMS R_(t)=1.17min using Method A, MS ESI calcd. for C₁₄H₁₀F₃N₂O₃ [M+H]⁺ 311.1, found310.9.

Example 44. Synthesis of Compound 44

Synthesis of A-47: To a mixture of A-47 (400 mg, 1.48 mmol) and K₂CO₃(613.79 mg, 4.44 mmol) in MeCN (15 mL) was added bromomethylbenzene(329.14 mg, 1.92 mmol). The reaction mixture was stirred at 20° C. for16 hours . The reaction mixture was diluted with EtOAc (10 mL), filteredthrough a Celite pad and eluted with EtOAc (10 mL). The residue waspurified by by flash chromatography on silica gel (EtOAc in PE=0% to 20%to 40%) to afford A-47 (150 mg, 0.4163 mmol) as a solid. ¹H NMR (CDCl₃,400 MHz) δ_(H)=8.13 (s, 1H), 7.90 (d, 2H), 7.48-7.35 (m, 5H), 7.29-7.24(m, 2H), 7.02 (s, 1H), 5.19 (s, 2H), 4.37 (s, 2H).

Synthesis of A-48: To a mixture of A-47 (180 mg, 0.5 mmol) and pyridine(118.54 mg, 1.5 mmol) in DCM (5 mL) was added ethyl carbonochloridate(65.05 mg, 0.6 mmol). The reaction mixture was stirred at 20° C. for 2hours . The reaction mixture was quenched with sat.NaHCO₃ (20 mL),extracted with EtOAc (20 mL×3). The combined organic phase was washedwith brine (20 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by by flash chromatography on silica gel (EtOAc inPE=0% to 20% to 40%) to afford A-48 (170 mg, 0.39 mmol) as a solid. ¹HNMR (DMSO-d6 400 MHz) δ_(H)=9.04 (s, 1H), 8.42-8.38 (m, 2H), 8.02 (d,2H), 7.57 (d, 2H), 7.46-7.32 (m, 5H), 5.33 (s, 2H), 4.20 (q, 2H), 1.27(t, 3H).

Synthesis of A-49: To a solution of A-49 (170 mg, 0.39 mmol) in THF (5mL) at 0° C. was added NaH (78.63 mg, 1.97 mmol). The reaction mixturewas stirred at 0° C. for 20 min. Then 2,2,2-trifluoroethyltrifluoromethanesulfonate (456.27 mg, 1.97 mmol) was added. The reactionmixture was stirred at 50° C. for 1 hour . The reaction was quenchedwith sat.NH₄Cl (20 mL), extracted with EtOAc (20 mL×3). The combinedorganic phase was washed with brine (20 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 10% to 30%) to afford A-49 (180 mg, 0.3499mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.64 (s, 1H), 8.17 (d,2H), 8.03 (s, 1H), 7.50-7.31 (m, 7H), 5.35 (s, 2H), 4.62-4.46 (m, 2H),4.12-3.99 (m, 2H), 1.13-0.94 (m, 3H).

Synthesis of A-50: A mixture of A-50 (180 mg, 0.35 mmol) and 10% wedPd/C (200 mg, 0.19 mmol) in Methanol (10 mL) under N₂ was degassed andrefilled with Hz. The reaction mixture was stirred under H₂ (15 psi,balloon) at 20° C. for 2 hours . The reaction mixture was diluted withEtOAc (10 mL), and filtered through a Celite pad to remove Pd/C, elutedwith EtOAc (10 mL). The filtrate was concentrated to afford A-50 (120mg, 0.28 mmol) as a oil. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.32 (s, 1H),8.09 (d, 2H), 7.83 (s, 1H), 7.42 (d, 2H), 4.52-4.40 (m, 2H), 4.11 (q,2H), 1.20-1.05 (m, 3H).

Synthesis of A-51: To a mixture of A-50 (120 mg, 0.28 mmol) in methanol(10 mL) and water (2 mL) was added NaOH (113.13 mg, 2.83 mmol). Thereaction mixture was stirred at 70° C. for 16 hours . The mixture wasacidified with 2M HCl to pH=5-6, then concentrated to give the residue,which was treated with THF (20 mL) and filtered. The filtrate wasconcentrated to afford A-51 (120 mg, 0.34 mmol, crude) as a solid. ¹HNMR (DMSO-d₆ 400 MHz) δ_(H)=8.19 (s, 1H), 8.09 (d, 2H), 7.90 (s, 1H),7.39 (d, 2H), 7.31 (s, 1H), 6.21 (t, 1H), 4.22-4.10 (m, 2H).

Synthesis of Compound 44: A mixture of A-51 (120 mg, 0.34 mmol) anddi(imidazol-1-yl)methanone (82.86 mg, 0.51 mmol) in THF (5 mL) washeated to 60° C. and stirred at 60° C. for 2 hours to give a solution .The reaction mixture was concentrated. The residue was purified by flashchromatography on silica gel (EtOAc in PE=0% to 20% to 40%) to affordCompound 44 (82.61 mg, 0.21 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz)δ_(H)=8.69 (s, 1H), 8.21 (s, 1H), 8.18 (d, 2H), 7.53 (d, 2H), 4.91 (q,2H). LCMS R_(t)=1.27 min using Method A, MS ESI calcd. for C₁₅H₉F₆N₂O₃[M+H]⁺ 379.1, found 378.9.

Example 45. Synthesis of Compound 45

Synthesis of A-51: To a solution of A-4 (200 mg, 0.68 mmol) in DMF (4mL) was added tert-butyl 2-bromopropanoate (169.98 mg, 0.81 mmol) andCs₂CO₃ (441.45 mg, 1.35 mmol). The resulting mixture was stirred at 55°C. for 2 hours. Saturated NH₄Cl aqueous (20 mL) and EtOAc (20 mL) wereadded to the reaction mixture. After separation, the organic layer waswashed with brine (20 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product that was purified by flashchromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to affordA-51 (235 mg, 0.55 mmol) as an oil. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=7.53(d, 2H), 7.33-7.28 (m, 4H), 7.13 (s, 1H), 5.05 (q, 1H), 1.75 (d, 3H),1.44 (s, 9H)

Synthesis of A-52: To a solution A-51 (235 mg, 0.56 mmol) in DCM (4 mL)was added TFA (2 mL, 26.93 mmol). The resulting solution was stirred at15° C. for 16 hours. The reaction solution was concentrated to give thecrude product A-52 (200 mg, 0.54 mmol) as a solid. ¹H NMR (DMSO-d₆ 400MHz) δ_(H)=7.80 (d, 2H), 7.66 (s, 1H), 7.50-7.44 (m, 4H), 5.23 (q, 1H),1.70 (d, 3H)

Synthesis of Compound 45: To a solution of A-52 (200 mg, 0.54 mmol) inDMF (4 mL) was added HATU (372.69 mg, 0.98 mmol), DIPEA (211.13 mg, 1.63mmol) and pyrrolidine (46.47 mg, 0.65 mmol). The resulting mixture wasstirred at 15° C. for 16 hours.

Saturated NH₄Cl aqueous (20 mL) and EtOAc (20 mL) were added to thereaction solution. After separation, the organic layer was washed withbrine (20 mL×2), dried over anhydrous Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified by Prep-HPLC(Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN);43-73% B over 10 minutes) to afford Compound 45 (77.94 mg, 0.19 mmol) asa solid. ¹H NMR (CDCl₃ DMSO-d₆ 400 MHz) δ_(H)=7.72 (d, 2H), 7.57 (d,1H), 7.51-7.40 (m, 4H), 5.27 (q, 1H), 3.63-3.56 (m, 1H), 3.40-3.34 (m,1H), 3.30-3.21 (m, 2H), 1.89-1.66 (m, 4H), 1.59 (d, 3H). LCMS R_(t)=1.27min using Method A, MS ESI calcd. for C₂₁H₂₀F₃N₂O₄ [M+H]⁺421.1, found421.0.

Example 46. Synthesis of Compound 46

To a solution of Compound 16 (140 mg, 0.40 mmol) in DMF (4 mL) was addedHATU (226.04 mg, 0.59 mmol), DIPEA (153.66 mg, 1.19 mmol) and2,2,2-trifluoroethanamine hydrochloride (107.42 mg, 0.79 mmol). Theresulting mixture was stirred at 15° C. for 16 hours . Saturated NH₄Claqueous (20 mL) and EtOAc (20 mL) was added to the reaction solution.After separation, the organic layer was washed with brine (20 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated to give the crudeproduct, which was purified by Prep-HPLC (Boston Green ODS (150 mm×30mm, 5 μm) A=H₂O (0.1% TFA) and B=CH₃CN); 42-72% B over 10 minutes) toafford Compound 46 (54.91 mg, 0.12 mmol) as a solid. ¹H NMR (DMSO-d₆ 400MHz) δ_(H)=9.02 (t, 1H), 7.77 (d, 2H), 7.60 (s, 1H), 7.50-7.43 (m, 4H),4.67 (s, 2H), 4.02-3.92 (m, 2H). LCMS R_(t)=1.21 min using Method A, MSESI calcd. for C₁₈H₁₃F₆N₂O₄ [M+H]⁺ 435.1, found 435.0.

Example 47. Synthesis of Compound 47

To the mixture of Compound 16 (180 mg, 0.51 mmol), HATU (290.62 mg, 0.76mmol) and DIPEA (131.71 mg, 1.02 mmol) in DMF (2 mL) was addedethanamine hydrochloride (49.86 mg, 0.61 mmol) and the mixture wasstirred at 20° C. for 16 hours . The mixture was diluted with sat. NH₄Cl(30 mL), extracted with EtOAc (30 mL×2). The combined organic phase waswashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product, which was purified by Prep-HPLC (PhenomenexGemini (150 mm×25 mm,10 um); A=H₂O (0.05% NH₄OH) and B=CH₃CN); 50-80% Bover 8 minutes) to afford Compound 47 (18.7 mg, 0.05 mmol) as a solid.¹H NMR (DMSO-d6 400 MHz) δ_(H)=8.29 (t, 1H), 7.78 (d, 2H), 7.59 (s, 1H),7.49-7.44 (m, 4H), 4.52 (s, 2H), 3.16-3.07 (m, 2H), 1.03 (t, 3H). LCMSR_(t)=1.17 min using Method A, MS ESI calcd. for C₁₈H₁₆F₃N₂O₄ [M+H]⁺381.1, found 381.0.

Example 48. Synthesis of Compound 48

Synthesis of A-53: To the mixture of A-18 (300 mg, 1.4 mmol) and Cs₂CO₃(909.21 mg, 2.79 mmol) in DMF (5 mL) was added iodoethane (435.27 mg,2.79 mmol) and the mixture was stirred at 20° C. for 16 hours . Themixture was diluted with H₂O (10 mL), extracted with EtOAc (10 mL×2).The combined organic phase was washed with brine (10 mL), dried overNa₂SO₄, filtered and the filtrate was concentrated to give the crudeproduct. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=10% to 30%) to afford A-53 (160 mg, 0.66 mmol)as a solid. ¹H NMR (DMSO-d6 400M Hz) δ_(H)=8.13-8.05 (m, 2H), 3.85 (q,2H), 1.26 (t, 3H)

Synthesis of Compound 48: A mixture of A-53 (90 mg, 0.37 mmol),[4-(trifluoromethoxy)phenyl]boronic acid (90.75 mg, 0.44 mmol),Pd(t-Bu₃P)₂ (28.15 mg, 0.06 mmol), and K₃PO₄ (155.93 mg, 0.73 mmol) in1,4-dioxane (2 mL) and water (0.2 mL) was stirred under N₂ at 90° C. for16 hours . The mixture was cooled to r.t., diluted with EtOAc (10 mL),filtered with silica gel, eluted with EtOAc (15 mL) and the filtrate wasconcentrated to give the crude product. The crude product was purifiedby Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 um) A=H₂O (10 mM NH₄HCO₃)and B=CH₃CN); 35-65% B over 10 minutes) to afford Compound 48 (81.71 mg,0.25 mmol) as a solid. ¹H NMR (DMSO-d₆ 400M Hz) δ_(H)=8.31 (d, 1H), 8.10(d, 1H), 7.88 (d, 2H), 7.51 (d, 2H), 3.92 (q, 2H), 1.31 (t, 3H). LCMSR_(t)=1.20 min using Method A, MS ESI calcd. for C₁₅H₁₂F₃N₂O₃ [M+H]⁺325.1, found 324.9.

Example 49. Synthesis of Compound 49

Synthesis of A-54: To the mixture of A-18 (300 mg, 1.4 mmol) and Cs₂CO₃(909.21 mg, 2.79 mmol) in DMF (3 mL) was added the2-(chloromethyl)pyrimidine (358.77 mg, 2.79 mmol) and the mixture wasstirred at 20° C. for 16 hours . The mixture was diluted with H₂O (10mL), and the mixture was extracted with EtOAc (10 mL×2). The combinedorganic phase was washed with brine (10 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product, which was purified by flashchromatography on silica gel (EtOAc in PE =20% to 50%) to afford A-54(170 mg, 0.55 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.79 (d,2H), 8.16 (d, 1H), 8.08 (d, 1H), 7.47 (t, 1H), 5.32 (s, 2H).

Synthesis of Compound 49: A mixture of A-54 (90 mg, 0.29 mmol),[4-(trifluoromethoxy)phenyl]boronic acid (71.95 mg, 0.35 mmol),Pd(t-Bu₃P)₂ (22.32 mg, 0.04 mmol), and K₃PO₄ (123.62 mg, 0.58 mmol) in1,4-dioxane (2 mL) and water (0.2 mL) was stirred under N₂ at 90° C. for16 hours . The mixture was cooled to r.t., diluted with EtOAc (10 ml),filtered with silica gel, eluted with EtOAc (15 mL) and the filtrate wasconcentrated to give the crude product, which was purified by Prep-HPLC(Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN);43-73% B over 10 minutes) to afford Compound 49 (69.86 mg, 0.18 mmol) asa solid. ¹H NMR (DMSO-d6 400 MHz) δ_(H)=8.79 (d, 2H), 8.36 (d, 1H), 8.11(d, 1H), 7.81 (d, 2H), 7.51-7.44 (m, 3H), 5.39 (s, 2H). LCMS R_(t)=1.15min using Method A, MS ESI calcd. for C₁₈H₁₂F₃N₄O₃ [M+H]⁺ 389.1, found389.0.

Example 50. Synthesis of Compound 50

To the mixture of A-4 (200 mg, 0.68 mmol) and Cs₂CO₃ (441.45 mg, 1.35mmol) in DMF (3 mL) was added 2-(chloromethyl)pyrimidine (174.19 mg,1.35 mmol) and the mixture was stirred at 20° C. for 16 hours . Themixture was diluted with H₂O (20 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with brine (10mL), dried over Na₂SO₄, filtered and the filtrate was concentrated togive the crude product, which was purified by Prep-HPLC (PhenomenexGemini (150 mm×25 mm,10 μm); A=H₂O (0.05% NH₄OH) and B=CH₃CN) 50-80% Bover 8 minutes) to afford Compound 50 (67.92 mg, 0.18 mmol) as a solid.¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.78 (d, 2H), 7.75 (d, 2H), 7.63 (d, 1H),7.51-7.42 (m, 5H), 5.37 (s, 2H). LCMS R_(t)=1.22 min using Method A, MSESI calcd. for C₁₉H₁₃F₃N₃O₃ [M+H]⁺ 388.1, found 388.0.

Example 51. Synthesis of Compound 51

To the mixture of A-4 (200 mg, 0.68 mmol) and2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (179.6 mg, 1.35 mmol) in ACN(3 mL) was added K2CO₃ (187.27 mg, 1.35 mmol) and the mixture wasstirred at 20° C. for 16 hours . The mixture was diluted with H₂O (20mL), and the mixture was extracted with EtOAc (20 mL×2). The combinedorganic phase was washed with brine (10 mL), dried over Na₂SO₄, filteredand the filtrate was concentrated to give the crude product, which waspurified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H₂O(0.05% NH₄OH) and B=CH₃CN); 58-68% B over 8 minutes) to afford Compound51 (52.03 mg, 0.13 mmol) as a solid. ¹H NMR (MeOD-d₄ 400 MHz) δ_(H)=7.70(d, 2H), 7.52 (d, 1H), 7.48-7.44 (m, 1H), 7.40-7.34 (m, 3H), 5.40 (s,2H), 2.52 (s, 3H). LCMS R_(t)=1.18 min using Method A, MS ESI calcd. forC₁₈H₁₃F₃N₃O₄ [M+H]⁺ 392.1, found 391.9.

Example 52. Synthesis of Compound 52

To a solution of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg,0.34 mmol) in THF (4 mL) was added methyl 3-hydroxypropanoate (105.44mg, 1.01 mmol), PPh₃ (177.1 mg, 0.68 mmol) and then DIAD (136.54 mg,0.68 mmol). The resulting mixture was stirred at 15° C. under N₂ for 16hours to give a light yellow solution. The reaction solution wasconcentrated to give the crude product. The crude product was purifiedby silica gel column (PE:EtOAc=0% to 10% to 20%) to give the product ofmethyl3-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]propanoate(100 mg, 0.2616 mmol, 77% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz)δ=8.01 (d, 2H), 7.48 (d, 2H), 7.32 (d, 2H), 4.33 (t, 2H), 3.69 (s, 3H),2.98 (t, 2H).

To a solution of methyl3-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]propanoate(100 mg, 0.26 mmol) in Ethanol (5 mL) was added hydrazine (25.15 mg,0.78 mmol). The resulting solution was stirred at 90° C. under N₂ for 16hours to give a yellow solution. The reaction solution was cooled toroom temperature and concentrated to give the crude product (100mg,0.1892 mmol) as a solid. The crude product was used to next stepdirectly. LCMS R_(t)=0.752 min in 1.5 min chromatography, MS ESI calcd.for C₁₆H₁₄F₃N₄O₄ [M+H]⁺ 383.1, found 383.0.

To a solution of3-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]propanehydrazide(100 mg, 0.19 mmol) in THF (5 mL) was added1,1-dimethoxy-N,N-dimethyl-ethanamine (37.8 mg, 0.28 mmol). Theresulting mixture was stirred at 55° C. under N₂ for 16 hours to give ayellow solution. The solution was concentrated to give a residue. Thenthe residue was re-dissolved in Toluene (5 mL) and TsOH.H₂O (5.4 mg,0.03 mmol) was added. The resulting mixture was stirred at 100° C. for16 hours to give a brown solution. The reaction mixture was cooled toroom temperature and concentrated to give the crude product. The crudeproduct was purified by Prep-TLC (PE:EtOAc=1:1) to give the product(54.07 mg, 0.1322 mmol, 70% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=7.95 (d, 2H), 7.48 (s, 2H), 7.32 (d, 2H), 4.44 (t, 2H), 3.44 (t,2H), 2.39 (s, 3H). LCMS R_(t)=1.197 min in 2.0 min chromatography, MSESI calcd. for C₁₈H₁₄F₃N₄O₄ [M+H]⁺ 407.1, found 407.0.

Example 53. Synthesis of Compounds 54 and 55

To a mixture of Compound 29 (100 mg, 0.34 mmol),tetrahydropyran-2-ylmethanol (117.65 mg, 1.01 mmol) and PPh₃ (177.1 mg,0.68 mmol) in THF (3 mL) was added DIAD (136.54 mg, 0.68 mmol) at 0° C.The mixture was allowed to warm to 25° C. and stirred for 16 hours underN2. The mixture was concentrated and purified by flash chromatography onsilica gel (EtOAC in PE=0 to 30%) to give Compound 94, which was furtherpurified by SFC (Chiralcel IC (250 mm×30 mm, 10 μm); A=CO₂ and B=EtOH(0.1% NH₃H₂O); 38° C.; 60 mL/min; 20% B over 9 minutes; multipleinjections) to afford Enantiomer 1, randomly assigned as Compound 54(R_(t)=6.5 min) and Enantiomer 2, randomly assigned as Compound 55(R_(t)=7.2 min). Compound 54 (36.04 mg, 0.09 mmol) ¹H NMR (CDCl₃, 400MHz), δ_(H)=7.93 (d, 2H), 7.39 (d, 2H), 7.25 (d, 2H), 4.10-4.01 (m, 1H),3.92-3.79 (m, 3H), 3.30 (dt, 1H), 1.85-1.77 (m, 1H), 1.68-1.60 (m, 1H),1.58-1.51 (m, 1H), 1.48-1.32 (m, 3H). LCMS R_(t)=1.37 min using MethodA, MS ESI calcd. for C₁₉H₁₈F₃N₂O₄ [M+H]⁺ 395.1, found 395.0. Compound 55(31.94 mg, 0.0810 mmol) ¹H NMR (CDCl₃+D₂O 400 MHz) δ_(H)=8.00 (d, 2H),7.47 (s, 2H), 7.32 (d, 2H), 4.18-4.09 (m, 1H), 4.00-3.87 (m, 3H), 3.38(dt, 1H), 1.95-1.85 (m, 1H), 1.75-1.68 (m, 1H), 1.67-1.59 (m, 1H),1.56-1.38 (m, 3H). LCMS R_(t)=1.34 min using Method A, MS ESI calcd. forC₁₉H₁₈F₃N₂O₄ [M+H]⁺ 395.1, found 395.0.

Example 54. Synthesis of Compound 56

To the mixture of Compound 5 (200 mg, 0.68 mmol),tetrahydropyran-4-ylmethanol (141.65 mg, 1.22 mmol) and PPh₃ (319.86 mg,1.22 mmol) in THF (5 mL) was added the DIAD (246.59 mg, 1.22 mmol) at 0°C. and the mixture was stirred under N₂ at 20° C. for 16 hours. Themixture was diluted with H₂O (20 mL), and extracted with EtOAc (20mL×2). The combined organic phase was washed with brine (10 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product, whichpurified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mMNH₄HCO₃) and B=CH₃CN); 56-86% B over 10 minutes) to afford Compound 56(78.49 mg, 0.20 mmol) as a solid. ¹H NMR (DMSO-d₆+D₂O 400 MHz)δ_(H)=7.75 (d, 2H), 7.52 (s, 1H), 7.44-7.36 (m, 4H), 3.83-3.69 (m, 4H),3.22 (br t, 2H), 2.13-1.95 (m, 1H), 1.54-1.43 (m, 2H), 1.32-1.22 (m,2H). LCMS R_(t)=1.29 min using Method A, MS ESI calcd. for C₂₀H₁₉F₃NO₄[M+H]⁺ 394.1, found 394.1.

Example 55. Synthesis of Compounds 57, 58, and 59

To a mixture of Compound 5 (150 mg, 0.51 mmol), DIAD (184.94 mg, 0.91mmol) and tetrahydropyran-2-ylmethanol (106.24 mg, 0.91 mmol) in THF (5mL) was added PPh₃ (239.89 mg, 0.91 mmol). The mixture was stirred at20° C. for 16 hours under N₂. The mixture was concentrated, the residuewas diluted with sat.NH₄Cl (20 mL), extracted with EtOAc (20 mL×2). Thecombined organic phase was washed with brine (10 mL), dried over Na₂SO₄and filtered. The filtrate was concentrated to give a residue, which waspurified by Prep-HPLC Xtimate C18 (250 mm×50 mm, 10 μm) A=H₂O (10 mMNH₄HCO₃) and B=CH₃CN); 50-80% B over 10 minutes) to afford Compound 57as a solid. ¹H NMR (CD₃CN-d₃ 400 MHz) δ_(H)=7.71 (d, 2H), 7.44-7.34 (m,4H), 7.32-7.26 (m, 1H), 3.92-3.79 (m, 3H), 3.77-3.68 (m, 1H), 3.38-3.30(m, 1H), 1.87-1.75 (m, 1H), 1.75-1.64 (m, 1H), 1.59-1.43 (m, 3H),1.42-1.28 (m, 1H). LCMS R_(t)=1.349 min using Method A, MS ESI calcd.for C₂₀H₁₉F₃NO₄ [M+H]⁺ 394.1, found 394.0. Compound 57 was purified bySFC (Chiralcel OJ (250 mm×30 mm, 5 μm); A=CO₂ and B=MeOH (0.1% NH₃H₂O);38° C.; 50 mL/min; 25% B over 9 minutes; multiple injections) to affordEnantiomer 1, randomly assigned as Compound 58 (R_(t)=7.05 min) andEnantiomer 2, randomly assigned as Compound 59 (Rt=7.95 min). Compound58 (7.55 mg, 0.019 mmol) ¹H NMR (CD₃CN-d₃ 400 MHz) δ_(H)=7.71 (d, 2H),7.45-7.34 (m, 4H), 7.31-7.26 (m, 1H), 3.94-3.80 (m, 3H), 3.76-3.67 (m,1H), 3.38-3.28 (m, 1H), 1.87-1.79 (m, 1H), 1.69 (d, 1H), 1.55-1.43 (m,3H), 1.38-1.29 (m, 1H). LCMS R_(t)=1.36 min using Method A, MS ESIcalcd. for C₂₀H₁₉F₃NO₄ [M+H]⁺ 394.1, found 394.1. Compound 59 (10.33 mg,0.025 mmol) ¹H NMR (CD₃CN-d₃ 400 MHz) δ_(H)=7.71 (d, 2H), 7.43-7.35 (m,4H), 7.31-7.26 (m, 1H), 3.89-3.80 (m, 3H), 3.76-3.69 (m, 1H), 3.39-3.29(m, 1H), 1.87-1.81 (m, 1H), 1.70 (d, 1H), 1.55-1.44 (m, 3H), 1.40-1.31(m, 1H). LCMS R_(t)=1.36 min using Method A, MS ESI calcd. forC₂₀H₁₉F₃NO₄ [M+H]⁺ 394.1, found 394.0.

Example 56. Synthesis of Compound 60, 61, and 62

To a mixture of Compound 29 (100 mg, 0.34 mmol),tetrahydrofuran-3-ylmethanol (103.44 mg, 1.01 mmol) and PPh₃ (177.1 mg,0.68 mmol) in THF (3 mL) was added DIAD (136.54 mg, 0.68 mmol) at 0° C.The mixture was allowed to warm to 25° C. and stirred for 16 hours underN₂. The mixture was concentrated to give Compound 60, which was purifiedby flash chromatography on silica gel (EtOAC in PE=0 to 30%) and SFC(ChiralCel OJ-H (150×4.6 mm, 5 μm); A=CO₂ and B=iPrOH (0.05% DEA); 40°C.; 2.5 mL/min; from 5% to 40% of B in 5.5min and hold 40%, for 3 min,then 5% of B for 1.5 min) to afford Enantiomer 1, randomly assigned asCompound 61 (R_(t)=3.615 min) and Enantiomer 2, randomly assigned asCompound 62 (R_(t)=3.483 min). Compound 61 (22.50 mg, 0.060 mmol). ¹HNMR (CDCl₃, 400 MHz) δ_(H)=8.00 (d, 2H), 7.49 (s, 2H), 7.33 (d, 2H),4.10-3.97 (m, 3H), 3.91-3.74 (m, 3H), 3.04-2.94 (m, 1H), 2.15-2.05 (m,1H), 1.90-1.80 (m, 1H). LCMS R_(t)=1.28 min using Method A, MS ESIcalcd. for C₁₈H₁₆F₃N₂O₄ [M+H]⁺ 381.1, found 381.0. Compound 62 (15.4mg,0.04 mmol). ¹H NMR (CDCl₃, 400 MHz), δ_(H)=8.00 (d, 2H), 7.49 (s,2H), 7.33 (d, 2H), 4.10-3.97 (m, 3H), 3.93-3.74 (m, 3H), 3.06-2.94 (m,1H), 2.15-2.04 (m, 1H), 1.91-1.79 (m, 1H). LCMS R_(t)=1.26 min usingMethod A, MS ESI calcd. for C₁₈H₁₆F₃N₂O₄ [M+H]⁺381.1, found 381.0.

Example 57. Synthesis of Compounds 63, 64, and 65

To a mixture of tetrahydrofuran-2-ylmethanol (103.44 mg, 1.01 mmol),Compound 29 (100 mg, 0.34 mmol) and PPh₃ (177.1 mg, 0.68 mmol) in THF (3mL) was added DIAD (136.54 mg, 0.68 mmol) at 0° C. The mixture wasallowed to warm to 25° C. and stirred for 16 hours under N₂. The mixturewas concentrated to give Compound 63, which was purified by flashchromatography on silica gel (EtOAc in PE=0 to 30%) and SFC (ChiralcelIC (250 mm×30 mm, 10 pm); A=CO₂ and B=EtOH (0.1% NH₃H₂O); 38° C.; 60mL/min; 25% B over 9 minutes; multiple injections) to afford Enantiomer1, randomly assigned as Compound 64 (Rt=5.8 min) and Enantiomer 2,randomly assigned as Compound 65 (R_(t)=7.2 min). Compound 64 (41.18 mg,0.11 mmol) ¹H NMR (CDCl₃, 400 MHz), δ_(H)=8.00 (d, 2H), 7.47 (s, 2H),7.32 (d, 2H), 4.60-4.51 (m, 1H), 4.15-4.07 (m, 1H), 4.02-3.91 (m, 2H),3.85-3.77 (m, 1H), 2.16-1.90 (m, 3H), 1.86-1.77 (m, 1H). LCMS R_(t)=1.29min using Method A, MS ESI calcd. for C₁₈H₁₆F₃N₂O₄ [M+H]⁺ 381.1, found381.0. Compound 65 (42.61 mg, 0.11 mmol) ¹H NMR (CDCl₃, 400 MHz),δ_(H)=8.03-7.96 (m, 2H), 7.47 (s, 2H), 7.32 (d, 2H), 4.60-4.51 (m, 1H),4.15-4.06 (m, 1H), 4.02-3.90 (m, 2H), 3.86-3.76 (m, 1H), 2.16-1.90 (m,3H), 1.86-1.74 (m, 1H). LCMS R_(t)=1.29 min using Method A, MS ESIcalcd. for C₁₈H₁₆F₃N₂O₄ [M+H]⁺381.1, found 381.0.

Example 58. Synthesis of Compounds 66 and 67

To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (4 mL) was addedtetrahydropyran-3-ylmethanol (117.65 mg, 1.01 mmol), PPh₃ (177.1 mg,0.68 mmol) and then DIAD (136.54 mg, 0.68 mmol). The resulting mixturewas stirred at 20° C. under N₂ for 16 hours . The reaction solution wasconcentrated to give the crude product, which was purified by flashchromatography on silica gel (EtOAc in PE=0% to 10% to 20%) and Prep-TLC(silica gel, PE:EtOAc=4:1) to afford A-58 (50 mg) as a solid. A-58 waspurified by SFC (Chiralcel AD (250 mm×30 mm, 5 μm); A=CO₂ and B=EtOH(0.1% NH₃H₂O); 38° C.; 50 mL/min; 30% B over 11 minutes; multipleinjections) to afford Enantiomer 1, randomly assigned as Compound 66(R_(t)=6.8 min) and Enantiomer 2, randomly assigned as Compound 67(R_(t)=9.2 min). Compound 66 (14.37 mg, 0.04 mmol) ¹H NMR (CDCl₃ 400MHz) δ_(H)=8.00 (d, 2H), 7.48 (s, 2H), 7.33 (d, 2H), 4.01-3.80 (m, 4H),3.56-3.35 (m, 2H), 2.43-2.30 (m, 1H), 1.96-1.85 (m, 1H), 1.82-1.72 (m,1H), 1.69-1.59 (m, 1H), 1.49-1.37 (m, 1H). LCMS R_(t)=1.32 min usingMethod A, MS ESI calcd. for C₁₉H₁₈F₃N₂O₄ [M+H]⁺ 395.1, found 395.0.Compound 67 (15.66 mg, 0.04 mmol) ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.00 (d,2H), 7.48 (s, 2H), 7.33 (d, 2H), 4.00-3.81 (m, 4H), 3.55-3.46 (m, 1H),3.41 (dd, 1H), 2.43-2.31 (m, 1H), 1.96-1.86 (m, 1H), 1.82-1.72 (m, 1H),1.69-1.59 (m, 1H), 1.49-1.37 (m, 1H). LCMS R_(t)=1.33 min using MethodA, MS ESI calcd. for C₁₉H₁₈F₃N₂O₄ [M+H]⁺395.1, found 395.1.

Example 59. Synthesis of Compounds 68, 69, and 70

To the mixture of Compound 5 (200 mg, 0.68 mmol),tetrahydrofuran-3-ylmethanol (124.54 mg, 1.22 mmol) and PPh₃ (319.86 mg,1.22 mmol) in THF (5 mL) was added DIAD (246.59 mg, 1.22 mmol). Themixture was stirred under N₂ at 20° C. for 16 hours. The mixture wasdiluted with sat.NH₄Cl (20 mL) and extracted with EtOAc (20 mL×2). Thecombined organic phase was washed with brine (10 mL), dried over Na₂SO₄,filtered and the filtrate was concentrated to give the crude product,which was purified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm);A=H₂O (0.05% NH₄OH) and B=CH₃CN); 55-85% B over 8 minutes) to affordCompound 68 (48.85 mg, 0.13 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz)δ_(H)=7.82 (d, 2H), 7.72 (s, 1H), 7.47 (d, 2H), 7.44 (d, 2H), 3.89 (d,2H), 3.85-3.79 (m, 1H), 3.71 (dd, 1H), 3.63 (q, 1H), 3.52 (dd, 1H),2.87-2.75 (m, 1H), 2.04-1.90 (m, 1H), 1.76-1.62 (m, 1H). LCMSR_(t)=1.244 min using Method A, MS ESI calcd. for C₁₉H₁₇F₃NO₄ [M+H]⁺380.1, found 380.2. The product was purified by SFC (Chiralcel AD (250mm×30 mm, 5 μm); A=CO₂ and B=MeOH (0.1% NH₃H₂O); 38° C.; 50 mL/min; 30%B over 12 minutes; multiple injections) to afford Enantiomer 1, randomlyassigned as Compound 69 (R_(t)=6.5 min) and Enantiomer 2, randomlyassigned as Compound 70 (Rt=10.5 min). Compound 69 (12.76 mg, 0.03 mmol)¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=7.85-7.79 (m, 2H), 7.72 (s, 1H),7.52-7.39 (m, 4H), 3.89 (d, 2H), 3.82 (dt, 1H), 3.71 (dd, 1H), 3.63 (q,1H), 3.51 (dd, 1H), 2.87-2.75 (m, 1H), 2.02-1.91 (m, 1H), 1.72-1.61 (m,1H). LCMS R_(t)=1.25 min using Method A, MS ESI calcd. for C₁₉H17F₃NO₄[M+H]⁺ 380.1, found 380.0. Compound 70 (12.37 mg, 0.03 mmol) ¹H NMR(DMSO-d₆ 400 MHz) δ_(H)=7.86-7.79 (m, 2H), 7.73 (s, 1H), 7.52-7.41 (m,4H), 3.89 (d, 2H), 3.82 (dt,), 3.72 (dd, 1H), 3.64 (q, 1H), 3.52 (dd,1H), 2.88-2.75 (m, 1H), 2.02-1.90 (m, 1H), 1.73-1.60 (m, 1H). LCMSR_(t)=1.26 min using Method A, MS ESI calcd. for C₁₉H₁₇F₃NO₄ [M+H]⁺380.1, found 379.9.

Example 60. Synthesis of Compound 71

Synthesis of Compound 71b: To a suspension of NaH (453.66 mg, 11.34mmol) in THF (50 mL) was added 2,2,2-trifluoroethanol (1.13 g, 11.34mmol) at 0° C., and the mixture was stirred at 20° C. for 1 hour. Thento the mixture was added 71a (2 g, 10.31 mmol), and the mixture wasstirred at 20° C. for another 4 hours . The mixture was quenched withsat.NH₄Cl (50 mL), and the mixture was extracted with EtOAc (100 mL×2).The combined organic phase was washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated to afford Compound 71b (1500 mg, 5.47mmol) as an oil. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.00 (d, 1H), 7.58 (dd,1H), 4.81 (q, 2H).

Synthesis of Compound 71c: A mixture of Compound 71b (1500 mg, 5.47mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(2780.26 mg, 10.95 mmol), Pd(dppf)Cl₂. CH₂Cl₂ (447.05 mg, 0.55 mmol) andKOAc (1074.49 mg, 10.95 mmol) in 1,4-dioxane (100 mL) was stirred at 90°C. for 16 hours . After cooling to r.t., the mixture was concentrated toa residue that was diluted with H₂O (50 mL) and extracted with EtOAc (50mL×2). The combined organic phase was washed with brine (50 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product, whichwas purified by flash chromatography on silica gel (EtOAc in PE=0 to 5%to 30%) column to afford Compound 71c (3800 mg, 11.835 mmol) as a solid.¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.26 (s, 1H), 7.72 (dd, 1H), 4.87 (q, 2H),1.35 (s, 12H)

Synthesis of A-60: To a solution of A-59 (240 mg, 1.12 mmol) in THF (4mL) was added ethanol (154.28 mg, 3.35 mmol), PPh₃ (585.58 mg, 2.23mmol) and then DIAD (451.45 mg, 2.23 mmol). The resulting mixture wasstirred at 20° C. under N₂ for 16 hours . The reaction solution wasconcentrated to give the crude product that was purified by flashchromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to affordA-60 (180 mg, 0.74 mmol) as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=7.33-7.20 (m, 2H), 4.01 (q, 2H), 1.44 (t, 3H).

Synthesis of Compound 71: A mixture of A-59 (100 mg, 0.41 mmol),Compound 71c (198.15 mg, 0.62 mmol), K₃PO₄ (174.69 mg, 0.82 mmol) andPd(t-Bu₃P)₂ (31.54 mg, 0.06 mmol) in 1,4-dioxane (5 mL) and water (0.50mL) was stirred at 80° C. under N₂ for 16 hours . The reaction mixturewas cooled to room temperature, filtered through Celite and eluted withEtOAc (10 mL×2). The filtrate was concentrated to give the crudeproduct, which was purified by flash chromatography on silica gel (EtOAcin PE=0% to 10% to 20%) to afford Compound 71 (125.91 mg, 0.35 mmol) asa solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.50 (d, 1H), 8.08 (dd, 1H),7.51-7.41 (m, 2H), 4.91 (q, 2H), 4.07 (q, 2H), 1.49 (t, 3H). LCMSR_(t)=1.26 min using Method A, MS ESI calcd. for C₁₅H₁₂F₄N₃O₃ [M+H]⁺358.1, found 358.0.

Example 61. Synthesis of Compounds 72, 73, and 74

To the mixture of Compound 5 (150 mg, 0.51 mmol), DIAD (184.94 mg, 0.91mmol) and tetrahydropyran-3-ylmethanol (106.24 mg, 0.91 mmol) in THF (5mL) was added PPh₃ (239.89 mg, 0.91 mmol). The mixture was stirred at20° C. for 16 hours under N₂. The mixture was concentrated, and theresidue was diluted with sat.NH₄Cl (20 mL), and extracted with EtOAc (20mL×2). The combined organic phase was washed with brine (10 mL), driedover Na₂SO₄ and filtered, and the filtrate was concentrated to give aresidue that was purified by Prep-HPLC (Xtimate C18 (250 mm×50 mm, 10μm) A=H₂O (10 mM % NH₃HCO₃) and B=CH₃CN); 55-85% B over 11.3 minutes) toafford Compound 72 (52.87 mg, 0.13 mmol) as an oil. ¹H NMR (CD₃CN 400MHz) δ_(H)=7.73 (d, 2H), 7.42-7.35 (m, 4H), 7.33-7.27 (m, 1H), 3.83-3.69(m, 4H), 3.43 (dt, 1H), 3.34-3.26 (m, 1H), 2.24-2.15 (m, 1H), 1.89-1.80(m, 1H), 1.73-1.64 (m, 1H), 1.58-1.46 (m, 1H), 1.46-1.34 (m, 1H). LCMSR_(t)=1.293 min using Method A, MS ESI calcd. for C₂₀H₁₉F₃NO₄ [M+H]⁺394.1, found 394.1. Compound 72 was purified by SFC (Chiralcel 0_(J)-3150×4.6 mm 3 μm Mobile phase: A: CO₂ B:ethanol (0.05% DEA)) to giveCompound 73 (11.22 mg, 0.0285 mmol) (Peakl, R_(t)=3.171 min in SFC,compound 73) as a solid and Compound 74 (8.6 mg, 0.0219 mmol) (Peak2,R_(t)=3.378 min in SFC) as a solid. Stereochemistry of compound 73 and74 was randomly assigned.

Compound 73

¹H NMR (CD₃CN-d₃ 400 MHz) δ_(H)=7.73 (d, 2H), 7.43-7.36 (m, 4H),7.33-7.28 (m, 1H), 3.82-3.70 (m, 4H), 3.48-3.40 (m, 1H), 3.30 (dd, 1H),2.24-2.17 (m, 1H), 1.90-1.78 (m, 1H), 1.72-1.64 (m, 1H), 1.57-1.48 (m,1H), 1.44-1.35 (m, 1H). LCMS R_(t)=1.30 min, MS ESI calcd. forC₂₀H₁₉F₃NO₄ [M+H]⁺ 394.1, found 394.2

Compound 74

¹H NMR CD₃CN-d₃ 400 MHz 6=7.78-7.69 (m, 2H), 7.47-7.33 (m, 4H),7.33-7.26 (m, 1H), 3.82-3.69 (m, 4H), 3.48-3.40 (m, 1H), 3.30 (dd, 1H),2.25-2.16 (m, 1H), 1.90-1.80 (m, 1H), 1.72-1.64 (m, 1H), 1.56-1.46 (m,1H), 1.45-1.38 (m, 1H). LCMS R_(t)=1.334 min in 2.0 min chromatography,MS ESI calcd. for C₂₀H₁₉F₃NO₄ [M+H]⁺ 394.1, found 394.1.

Example 62. Synthesis of Compound 75

To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (5 mL) was addedMeOH (32.41 mg, 1.01 mmol), PPh₃ (177.1 mg, 0.68 mmol) and then DIAD(136.54 mg, 0.68 mmol). The resulting mixture was stirred at 15° C.under N₂ for 16 hours to give a solution . The solution was concentratedto give the crude product, which was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 10% to 20%) to afford Compound 75 (45.57mg, 0.15 mmol) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.02 (d, 2H),7.48 (s, 2H), 7.33 (d, 2H), 3.55 (s, 3H). LCMS R_(t)=1.26 min usingMethod A, MS ESI calcd. for C₁₄H₁₀F₃N₂O₃ [M+H]⁺ 311.1, found 310.9.

Example 63. Synthesis of Compound 76

To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (5 mL) was addedEtOH (46.69 mg, 1.01 mmol), PPh₃ (177.1 mg, 0.68 mmol) and then DIAD(136.54 mg, 0.68 mmol). The resulting mixture was stirred at 15° C.under N₂ for 16 hrs. The solution was then concentrated to give thecrude product, which was purified by flash chromatography on silica gel(EtOAc in PE=0 to 20% to 50%) to afford Compound 76 (86.45 mg, 0.27mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.18 (d, 2H), 7.84-7.74(m, 2H), 7.49 (d, 2H), 3.94 (q, 2H), 1.37 (t, 3H). LCMS R_(t)=1.32 minusing Method A, MS ESI calcd. for C₁₅H₁₂F₃N₂O₃ [M+H]⁺ 325.1, found324.9.

Example 64. Synthesis of Compound 77

Synthesis of A-61: To a mixture of A-18 (400 mg, 1.86 mmol) and Cs₂CO₃(1212.28 mg, 3.72 mmol) in DMF (5 mL) was added 2-bromopropane (457.64mg, 3.72 mmol). The mixture was stirred at 50° C. for 16 hours . Themixture was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL×2).The combined organic phase was washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated to give the crude product that waspurified by flash chromatography on silica gel (EtOAc in PE=0 to 20% to50%) to afford A-60 (200 mg, 0.70 mmol) as a solid, ¹H NMR (CDCl₃, 400MHz) δ_(H)=8.10 (d, 1H), 7.47 (d, 1H), 4.57 (spt, 1H), 1.56-1.50 (m,6H). LCMS R_(t)=0.73 min using Method B, MS ESI calcd. for C₉H₁₀BrN₂O₂[M+H]⁺257.0, found 256.7.

Synthesis of Compound 77: A mixture of A-60 (200 mg, 0.78 mmol),[4-(trifluoromethoxy)phenyl]boronic acid (192.25 mg, 0.93 mmol),Pd(t-Bu₃P)₂ (79.52 mg, 0.16 mmol) and K₃PO₄ (330.33 mg, 1.56 mmol) in1,4-dioxane (5 mL) and water (1 mL) was stirred at 90° C. for 16 hours .After cooling, the mixture was filtered through silica gel and elutedwith EtOAc (20 mL×2). The filtrate was concentrated and diluted withEtOAc (30 mL), washed with water (10 mL×2) and brine (10 mL), dried overNa₂SO₄, filtered and concentrated to give the crude product, which waspurified by Prep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H₂O(0.05% NH₄OH) and B=CH₃CN); 55-85% B over 8 minutes) to give Compound 77(24.22 mg, 0.07 mmol) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.19 (d,1H), 7.57 (d, 2H), 7.46 (d, 1H), 7.36 (d, 2H), 4.63 (spt, 1H), 1.60 (d,6H). LCMS R_(t)=1.23 min using Method A, MS ESI calcd. for C₁₆H₁₄F₃N₂O₃[M+H]⁺ 339.1, found 338.9.

Example 65. Synthesis of Compound 78

To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (5 mL) was addedpropan-2-ol (60.87 mg, 1.01 mmol), PPh₃ (177.1 mg, 0.68 mmol) and DIAD(136.54 mg, 0.68 mmol). The resulting mixture was stirred at 15° C.under N₂ for 16 hours . The reaction solution was concentrated to givethe crude product, which was purified by flash chromatography on silicagel (EtOAc in PE=0% to 10% to 20%) to afford Compound 78 (49.62 mg, 0.15mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.17 (d, 2H), 7.82-7.73(m, 2H), 7.49 (d, 2H), 4.62 (spt, 1H), 1.58 (d, 6H). LCMS R_(t)=1.34 minusing Method A, MS ESI calcd. for C₁₆H₁₄F₃N₂O₃ [M+H]⁺ 339.1, found338.9.

Example 66. Synthesis of Compound 79

Synthesis of A-62: To a solution of Compound 29 (200 mg, 0.68 mmol) inTHF (5 mL) was added tert-butyl 2-hydroxyacetate (267.71 mg, 2.03 mmol),PPh₃ (354.21 mg, 1.35 mmol) and DIAD (273.07 mg, 1.35 mmol). Theresulting mixture was stirred at 15° C. under N₂ for 16 hours . Thereaction solution was concentrated, and the residue was purified byflash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) toafford A-61 (270 mg, 0.66 mmol) as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=7.97 (d, 2H), 7.49 (s, 2H), 7.30 (d, 2H), 4.62 (s, 2H), 1.49 (s,9H).

Synthesis of A-63: To a solution of A-61 (270 mg, 0.66 mmol) in DCM (4mL) was added TFA (2 mL, 26.93 mmol). The resulting mixture was stirredat 15° C. for 16 hours . The reaction solution was concentrated toafford A-62 (220 mg, 0.62 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz)δ_(H)=8.17 (d, 2H), 7.91-7.86 (m, 1H), 7.85-7.80 (m, 1H), 7.48 (d, 2H),4.67 (s, 2H).

Synthesis of Compound 79: To a solution of A-62 (110 mg, 0.31 mmol) inDMF (3 mL) was added HATU (177.11 mg, 0.47 mmol), DIPEA (120.4 mg, 0.93mmol) and pyrrolidine (26.5 mg, 0.37 mmol). The resulting mixture wasstirred at 15° C. for 16 hours. Saturated NH₄Cl aqueous (20 mL) andEtOAc (20 mL) was added to the reaction solution. After separation, theorganic layer was washed with brine (20 mL×2), dried over anhydrousNa₂SO₄, filtered and concentrated, and the residue was purified byPrep-HPLC(Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) andB=CH₃CN); 49-69% B over 8 minutes) to afford Compound 79 (21.73 mg, 0.05mmol) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=7.94 (d, 2H), 7.47 (q,2H), 7.29 (d, 2H), 4.70 (s, 2H), 3.61 (t, 2H), 3.54 (t, 2H), 2.09 (quin,2H), 1.92 (quin, 2H). LCMS R_(t)=1.21 min using Method A, MS ESI calcd.for C₁₉H₁₇F₃N304 [M+H]⁺ 408.1, found 407.9.

Example 67. Synthesis of Compound 80

Synthesis of Compound 80: To a solution of Compound 16 (100 mg, 0.28mmol) in DMF (3 mL) was added HATU (161.46 mg, 0.42 mmol), DIPEA (109.76mg, 0.85 mmol) and 2,2,2-trifluoro-N-methyl-ethanamine hydrochloride(50.8 mg, 0.34 mmol). The resulting mixture was stirred at 15° C. for 16hours. Saturated NH₄Cl aqueous (20 mL) and EtOAc (20 mL) were added tothe reaction solution. After separation, the organic layer was washedwith brine (20 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product, which was purified by Prep-HPLC(Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN);55-75% B over 10.5 minutes) to afford Compound 80 (55.77 mg, 0.12 mmol)as a solid ¹H NMR (CDCl₃, 400 MHz) δ_(H)=7.74 (m, 2H), 7.65-7.40 (m,5H), 5.00 (s, 1.6H), 4.91 (s, 0.4H), 4.47 (m, 0.4H), 4.19 (m, 1.6H),3.25 (s, 2.4H), 2.96 (s, 0.6H). Note that rotamers were observed in the¹H NMR spectrum of this compound. LCMS R_(t)=1.25 min using Method A, MSESI calcd. for C₁₉H₁₅F₆N₂O₄ [M+H]⁺ 449.0931, found 449.0990.

Example 68. Synthesis of Compound 84

To the mixture of Compound 5 (150 mg, 0.51 mmol), DIAD (184.94 mg, 0.91mmol) and pyrimidin-5-ylmethanol (100.71 mg, 0.91 mmol) in THF (5 mL)was added PPh₃ (239.89 mg, 0.91 mmol) and the mixture was stirred at 20°C. for 16 hours under N2. The mixture was concentrated, the residue wasdiluted with NH₄Cl (20 mL) extracted with EtOAc (20 mL×2). The combinedorganic phase was washed with brine (10 mL), dried over Na₂SO₄,filtered, and concentrated to give a residue that was purified byPrep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) andB=CH₃CN); 40-70% B over 10 minutes) to afford Compound 84 as a solid. ¹HNMR (DMSO-d₆ 400 MHz) δ_(H)=9.14 (s, 1H), 8.92 (s, 2H), 7.81-7.74 (m,3H), 7.51-7.44 (m, 4H), 5.19 (s, 2H). LCMS R_(t)=1.19 min using MethodA, MS ESI calcd. for C₁₉H_(D)F₃N₃O₃ [M+H]⁺ 388.1, found 388.0.

Example 69. Synthesis of Compound 85

To the a mixture of Compound 15 (100 mg, 0.28 mmol), HATU (161.46 mg,0.42 mmol) and DIPEA (73.17 mg, 0.57 mmol) in DMF (2 mL) was addedN-methylethanamine (20.08 mg, 0.34 mmol) and the mixture was stirred at20° C. for 16 hours . The mixture was diluted with sat. NH₄Cl (10 mL),extracted with EtOAc (10 mL×2), and the combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, and filtered. The filtratewas concentrated to give a residue that was purified by Prep-HPLCXtimate C18 (250 mm×50 mm, 10 μm) A=H₂O (10 mM NH₃HCO₃) and B=CH₃CN);50-70% B over 7 minutes) to afford Compound 85 (25.86 mg 0.0656 mmol) asa solid. ¹H NMR (DMSO-d₆+D₂O 400 MHz) δ_(H)=7.72 (d, 2H), 7.52-7.35 (m,5H), 4.79 (d, 2H), 3.40 (d, 0.9 H), 3.28 (d, 1H), 3.03 (s, 1.7H), 2.79(s, 1.3H), 1.18 (t, 1.3H), 0.98 (t, 1.7H). Note that rotamers wereobserved in the ¹H NMR spectrum of this compound. LCMS R_(t)=1.21 minusing Method A, MS ESI calcd. for C₁₉H₁₈F₃N₂O₄ [M+H]⁺ 395.1, found395.0.

Example 70. Synthesis of Compound 86

To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (5 mL) was added2,2-difluoroethanol (83.1 mg, 1.01 mmol), PPh₃ (177.1 mg, 0.68 mmol) andDIAD (136.54 mg, 0.68 mmol). The resulting mixture was stirred at 15° C.under N₂ for 16 hours . The reaction solution was concentrated to give aresidue that was purified by flash chromatography on silica gel (EtOAcin PE=0% to 10% to 20%) to afford Compound 86 (77.26 mg, 0.21 mmol) as asolid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.03-7.97 (m, 2H), 7.53 (d, 2H),7.33 (d, 2H), 6.30 (tt, 1H), 4.37 (dt, 2H). LCMS R_(t)=1.25min usingMethod A, MS ESI calcd. for C₁₅H₁₀F₅N₂O₃ [M+H]⁺ 361.1, found 361.0.

Example 71. Synthesis of Compound 87

To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (4 mL) was added2-pyrimidin-2-ylethanol (125.73 mg, 1.01 mmol), PPh₃ (177.1 mg, 0.68mmol) and DIAD (136.54 mg, 0.68 mmol). The resulting mixture was stirredat 15° C. under N₂ for 16 hours . The reaction solution was concentratedto give a residue that was purified by flash chromatography on silicagel (EtOAc in PE=0% to 10% to 20%) to afford Compound 87 (84.69 mg, 0.21mmol) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.62 (d, 2H), 7.95 (d,2H), 7.44 (s, 2H), 7.30 (d, 2H), 7.10 (t, 1H), 4.53 (t, 2H), 3.56 (t,2H). LCMS R_(t)=1.20 min using Method A, MS ESI calcd. for C₁₉H₁₄F₃N₄O₃[M+H]⁺ 403.1, found 403.1.

Example 72. Synthesis of Compound 88

To a solution of A-62 (110 mg, 0.31 mmol) in DMF (3 mL) was added HATU(177.11 mg, 0.47 mmol), DIPEA (120.4 mg, 0.93 mmol), and thenN-methylmethanamine hydrochloride (30.38 mg, 0.37 mmol). The resultingmixture was stirred at 20° C. for 16 hours . Saturated NH₄Cl aqueous (20mL) and EtOAc (20 mL) was added to the reaction solution. Afterseparation, the organic layer was washed with brine (20 mL×2), driedover anhydrous Na₂SO₄, filtered and concentrated to give a residue thatwas purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10mM NH₄HCO₃) and B=CH₃CN); 47-67% B over 8 minutes) to afford Compound 88(34.39 mg, 0.09 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.15(d, 2H), 7.87 (d, 1H), 7.79 (d, 1H), 7.47 (d, 2H), 4.86 (s, 2H), 3.14(s, 3H), 2.86 (s, 3H). LCMS R_(t)=1.16 min using Method A, MS ESI calcd.for C₁₇H₁₅F₃N₃O₄ [M+H]⁺ 382.1, found 382.0.

Example 73. Synthesis of Compounds 89, 99, and 100

To a solution of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (200 mg,0.68 mmol) in THF (5 mL) was added PPh₃ (354.21 mg, 1.35 mmol),4-hydroxybutan-2-one (178.48 mg, 2.03 mmol) and then DIAD (273.07 mg,1.35 mmol). The resulting solution was stirred at 20° C. under N₂ for 16hours to give a solution. The reaction solution was concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give theproduct (200 mg, 0.5231 mmol) as a solid. ¹H NMR (CDCl₃ 400 MHz)δ_(H)=8.00 (d, 2H), 7.47 (d, 2H), 7.32 (d, 2H), 4.28 (t, 2H), 3.11 (t,2H), 2.23 (s, 3H). LCMS R_(t)=0.881 min in 1.5 min chromatography, MSESI calcd. for C₁₇H₁₄F₃N₂O₄ [M+H]⁺ 367.1, found 367.0.

To a solution of3-(3-oxobutyl)-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-2-one(200 mg, 0.55 mmol) in THF (20 mL) was added NaBH₄ (41.31 mg, 1.09mmol). The resulting mixture was stirred at 15° C. for 0.5 h to give asuspension. Saturated NH₄Cl aqueous (20 mL) and EtOAc (30 mL) was addedto the reaction suspension. After separated, the organic layer waswashed with brine (20 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) togive the product .

The product was purified by SFC (AD (250 mm×30 mm, 5 μm; A=CO₂ and B=EtOH (0.1% NH₃H₂O); 38° C.; 50 mL/min; 20% B; 10 min run; 15injections, Rt of peak 1=8.0 min, Rt of Peak 2=8.6 min) to give Compound99 (3.02 mg, 0.0079 mmol) (Peak 1, Rt=3.250 min in SFC) as a solid andCompound 100 (10.09 mg, 0.0274 mmol) (Peak 2: Rt=3.381 min in SFC) as asolid. The stereochemistry of compound 99 and compound 100 was randomlyassigned

Compound 99 ¹H NMR (CDCl₃, 400 MHz) δ_(H)=7.96 (d, 2H), 7.56-7.48 (m,2H), 7.34 (d, 2H), 4.29-4.11 (m, 2H), 3.86-3.70 (m, 1H), 3.67-3.56 (m,1H), 2.10-1.99 (m, 1H), 1.90-1.76 (m, 1H), 1.25 (d, 3H). LCMSR_(t)=1.201 min in 2.0 min chromatography, MS ESI calcd. forC₁₇H₁₆F₃N₂O₄[M+H]⁺ 369.1, found 369.0.

Compound 100 ¹H NMR (CDCl₃, 400 MHz) δ_(H)=7.95 (d, 2H), 7.55-7.46 (m,2H), 7.33 (d, 2H), 4.28-4.10 (m, 2H), 3.81-3.69 (m, 1H), 3.63-3.52 (m,1H), 2.09-1.97 (m, 1H), 1.88-1.75 (m, 1H), 1.24 (d, 3H). LCMSR_(t)=1.226 min in 2.0 min chromatography, MS ESI calcd. forC₁₇H₁₆F₃N₂O₄ [M+H]⁺ 369.1, found 369.0.

Example 74. Synthesis of Compound 90

Synthesis of A-66: To a solution of Compound 29 (150 mg, 0.51 mmol) inTHF (4 mL) was added 3-[tert-butyl(dimethyl)silyl]oxypropan-1-ol (289.2mg, 1.52 mmol), PPh₃ (265.65 mg, 1.01 mmol) and DIAD (204.8 mg, 1.01mmol). The resulting mixture was stirred at 15° C. under N₂ for 16 hours. The reaction solution was concentrated to give a residue that waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to20%) to afford A-66 (180 mg, 0.38 mmol) as a solid. ¹H NMR (CDCl₃, 400MHz) δ_(H)=8.02 (d, 2H), 7.49-7.43 (m, 2H), 7.31 (d, 2H), 4.13 (t, 2H),3.77 (t, 2H), 2.17-2.08 (m, 2H), 0.89 (s, 9H), 0.04 (s, 6H).

Synthesis of Compound 90: To a solution of A-66 (40 mg, 0.09 mmol) inmethanol (2 mL) was added HCl/dioxane (2 mL, 0.09 mmol). The resultingsolution was stirred at 15° C. for 16 hours . The reaction wasconcentrated to give a residue that was purified by Prep-TLC (silicagel, PE:EtOAc=1:1) to afford Compound 90 (21.59 mg, 0.06 mmol) as asolid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.17 (d, 2H), 7.83-7.74 (m, 2H),7.49 (d, 2H), 4.58 (t, 1H), 3.96 (t, 2H), 3.52 (q, 2H), 1.97 (quin, 2H).LCMS R_(t)=1.16 min using Method A, MS ESI calcd. for C₁₆H₁₄F₃N₂O₄[M+H]⁺ 355.1, found 355.0.

Example 75. Synthesis of Compound 91

To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (4 mL) was added1,1,1,2,2-pentadeuterio-2-deuteriooxy-ethane (52.78 mg, 1.01 mmol), PPh₃(177.1 mg, 0.68 mmol) and then DIAD (136.54 mg, 0.68 mmol). Theresulting mixture was stirred at 15° C. under N₂ for 16 hours . Thereaction solution was concentrated to give a residue that was purifiedby flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) toafford Compound 91 (49.41 mg, 0.15 mmol) as a solid. ¹H NMR (DMSO-d6 400MHz) δ_(H)=8.18 (d, 2H), 7.84-7.74 (m, 2H), 7.49 (d, 2H). LCMSR_(t)=1.29 min using Method A, MS ESI calcd. for C₁₅H₇D₅F₃N₂O₃ [M+H]⁺330.1108, found 330.1104.

Example 76. Synthesis of Compound 92

Synthesis of A-67: To a mixture of A-18 (173.22 mg, 1.4 mmol) and PPh₃(439.18 mg, 1.67 mmol) in THF (3 mL) under N₂ was added DEAD (291.6 mg,1.67 mmol) drop-wise at 0° C. The reaction mixture was then stirred at20° C. for 16 hours . The mixture was concentrated to give a residuethat was purified by flash chromatography on silica gel (EtOAc in PE=0to 50% to 100%) to afford A-67 (250 mg, 0.26 mmol) as a solid. LCMSR_(t)=0.67 min using Method B, MS ESI calcd. for C₁₂H₁₀BrN₄O₂[M+H+2]⁺323.0, found 322.9.

Synthesis of Compound 92: A mixture of A-67 (250 mg, 0.78 mmol), K₃PO₄(330.55 mg, 1.56 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (192.38mg, 0.93 mmol) and Pd(t-Bu₃P)₂ (79.57 mg, 0.16 mmol) in 1,4-dioxane (5mL) and water (1 mL) was stirred at 90° C. for 16 hours under N2. Aftercooling, the mixture was filtered through silica gel and eluted withEtOAc (20 mL×2). The filtrate was concentrated and diluted with EtOAc(30 mL), washed with water (10 mL×2) and brine (10 mL), dried overNa₂SO₄, filtered and concentrated to give a residue that was purified byPrep-HPLC (Phenomenex Gemini (150 mm×25 mm,10 μm); A=H₂O (0.05% NH₄OH)and B=CH₃CN); 53-63% B over 8 minutes) to afford Compound 92 (50.95 mg,0.12 mmol) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.65 (d, 2H), 8.17(d, 1H), 7.54 (d, 2H), 7.40 (d, 1H), 7.35 (d, 2H), 7.17 (t, 1H), 4.44(t, 2H), 3.50 (t, 2H). LCMS R_(t)=1.15 min using Method A, MS ESI calcd.for C₁₉H₁₄F₃N403 [M+H]⁺ 403.1, found 403.0.

Example 77. Synthesis of Compound 93

To a solution of Compound 29 (100 mg, 0.34 mmol) in THF (4 mL) was addedtrideuterio(deuteriooxy)-methane (36.53 mg, 1.01 mmol), PPh₃ (177.1 mg,0.68 mmol) and then DIAD (136.54 mg, 0.68 mmol). The resulting mixturewas stirred at 15° C. under N₂ for 16 hours . The reaction solution wasconcentrated to give a residue that was purified by flash chromatographyon silica gel (EtOAc in PE=0% to 10% to 20%) to afford Compound 93(68.88 mg, 0.22 mmol) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.19(d, 2H), 7.84-7.74 (m, 2H), 7.49 (d, 2H). LCMS R_(t)=1.23 min usingMethod A, MS ESI calcd. for C₁₄H₇D3F₃N₂O₃ [M+H]⁺ 314.0826, found314.0815.

Example 78. Synthesis of Compound 96

To the mixture of 5-bromo-3H-1,3-benzoxazol-2-one (300 mg, 1.4 mmol) andCs₂CO₃ (913.37 mg, 2.8 mmol) in DMF (5 mL) was added iodoethane (437.26mg, 2.8 mmol) and the mixture was stirred at 20° C. for 16 hours. Themixture was diluted with H₂O (20 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with brine (10mL), dried over Na₂SO₄, filtered and the filtrate was concentrated togive the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=20% to 50%) to give theproduct of 5-bromo-3-ethyl-1,3-benzoxazol-2-one (220 mg, 0.908 mmol,645% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=7.24 (dd, 1H),7.13 (d, 1H), 7.08 (d, 1H), 3.87 (q, 2H), 1.39 (t, 3H).

A mixture of 5-bromo-3-ethyl-1,3-benzoxazol-2-one (200 mg, 0.83 mmol),3-fluoro (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (397.92mg, 1.24 mmol), K₃PO₄ (350.81 mg, 1.65 mmol), and Pd(t-Bu₃P)₂ (63.33 mg,0.12 mmol) in 1,4-Dioxane (3 mL) and Water (0.3 mL) was stirred at 90°C. for 16 hours under N₂ to give a mixture. The mixture was cooled tor.t., diluted with EtOAc (20 mL), filtered through silica gel and elutedwith EtOAc (20 mL). The filtrate was concentrated to give the crudeproduct. The crude product was purified by Prep-HPLC (column: WatersXbridge 150*25 5u; mobile phase: [water(10 mM NH₄HCO₃)-ACN]; B%:51%-81%, 7 min) to give the product (134.4 mg, 0.3712 mmol, 45% yield)as a solid. ¹H NMR DMSO-d₆ 400 MHz 6=8.41 (d, 1H), 8.25 (dd, 1H), 7.74(d, 1H), 7.54-7.41 (m, 2H), 5.14 (q, 2H), 3.91 (q, 2H), 1.30 (t, 3H).LCMS R_(t)=1.254 min in 2.0 min chromatography, MS ESI calcd. forC₁₆H₁₃F₄N₂O₃ [M+H]⁺ 357.1, found 357.0.

Example 79. Synthesis of Compound 97 and Compound 98

To a solution of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one(400 mg, 1.35 mmol) in THF (5 mL) was added PPh₃ (710.79 mg, 2.71 mmol),and 4-hydroxybutan-2-one (358.16 mg, 4.06 mmol), then DIAD (547.98 mg,2.71 mmol). The resulting solution was stirred at 20° C. under N₂ for 16hours to give a solution. The mixture was diluted with H₂O (20 mL), andthe mixture was extracted with EtOAc (20 mL×2). The combined organicphase was washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby Prep-HPLC (column: Waters Xbridge 150*25 5 u, mobile phase: water (10mM NH₄HCO₃)-CAN, B%: 55%-75%, 7 min) to give the product (150 mg, 0.410mmol, 30% yield) as a solid. ¹H NMR DMSO-d₆ 400 MHz δ_(H)=7.82 (d, 2H),7.69 (s, 1H), 7.47 (d, 2H), 7.42 (s, 2H), 4.04 (t, 2H), 3.00 (t, 2H),2.13 (s, 3H).

To a solution of3-(3-oxobutyl)-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one (150mg, 0.41 mmol) in methanol (2 mL) was added NaBH₄ (31.07 mg, 0.82 mmol).The resulting mixture was stirred at 20° C. for 0.5 h to give asuspension. Saturated NH₄Cl aqueous (10 mL) and EtOAc (10 mL) was addedto the reaction suspension. After separation, the organic layer waswashed with brine (5 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the product (120 mg).

The product was purified by SFC (AD (250 mm×30 mm, 5 μm), A=CO₂ andB=EtOH (0.1% NH₃H₂O); 38° C.; 50 mL/min; 20% B; 9 min run; 12injections, Rt of peak 1=6.7 min,

Rt of Peak 2=7.8 min) to give compound 97 (29.78 mg, 0.0811 mmol)(Peakl, R_(t)=3.090 min in SFC) as oil and compound 98 (31.57 mg, 0.086mmol) (Peak2, R_(t)=3.301 min in SFC) as oil.

Compound 97 ¹H NMR DMSO-d₆ 400 MHz δ=7.81 (d, 2H), 7.60 (s, 1H), 7.47(d, 2H), 7.42 (s, 2H), 4.63 (d, 1H), 3.98-3.89 (m, 2H), 3.71-3.64 (m,1H), 1.85-1.66 (m, 2H), 1.10 (d, 3H). LCMS R_(t)=1.228min in 2.0 minchromatography, MS ESI calcd. for C₁₈H₁₇F₃NO₄ [M+H]⁺ 368.1, found 368.0.

Compound 98 ¹H NMR DMSO-d₆ 400 MHz 6=7.81 (d, 2H), 7.60 (s, 1H), 7.47(d, 2H), 7.42 (s, 2H), 4.64 (d, 1H), 3.97-3.91 (m, 2H), 3.70-3.64 (m,1H), 1.84-1.67 (m, 2H), 1.10 (d, 3H). LCMS R_(t)=1.230 min in 2.0 minchromatography, MS ESI calcd. for C₁₈H₁₇F₃NO₄ [M+H]⁺ 368.1, found 368.0.

Example 80. Synthesis of Compound 101

A mixture of 3-benzyloxy-6-bromo-2-nitro-pyridine (1.9 g, 6.15 mmol),[4-(trifluoromethoxy)phenyl]boronic acid (1.52 g, 7.38 mmol), K₃PO₄(2.61 g, 12.29 mmol) and Pd(t-Bu₃P)₂ (471.17 mg, 0.92 mmol) in1,4-Dioxane (20 mL) and Water (2 mL) was stirred at 80° C. under N₂ for16 hours to give a suspension. The reaction mixture was cooled to roomtemperature and filtered through Celite. The filtrate was concentratedto give the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give theproduct (1000 mg, 2.56 mmol, 42% yield) as a solid. ¹H NMR (DMSO-d₆ 400MHz) δ_(H)=8.36 (d, 1H), 8.17-8.07 (m, 3H), 7.53-7.31 (m, 7H), 5.42 (s,2H).

To a solution of3-benzyloxy-2-nitro-6-[4-(trifluoromethoxy)phenyl]pyridine (1 g, 2.56mmol) in Methanol (50 mL) was added Pd/C (200 mg, 1.89 mmol). Theresulting mixture was stirred at 20° C. under molecular hydrogen (512.36mg, 253.64 mmol) (15 psi) for 3 hours to give a black suspension. Thereaction mixture was filtered through Celite. The filtrate wasconcentrated to give the crude product (690 mg, 2.55 mmol,) as a solid.¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=7.98 (d, 2H), 7.35 (d, 2H), 7.01 (d, 1H),6.91 (d, 1H), 5.59 (s, 2H).

To a solution of 2-amino-6-[4-(trifluoromethoxy)phenyl]pyridin-3-ol (690mg, 2.55 mmol) in THF (30 mL) was added di(imidazol-1-yl)methanone(496.87 mg, 3.06 mmol). The resulting mixture was stirred at 60° C. for16 hours to give a solution. The reaction mixture was cooled to roomtemperature and concentrated to give the crude product. The crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=20% to 40% to 50%) to give the product of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (700 mg,2.3633 mmol, 92.548% yield) as a solid. ¹H NMR DMSO-d₆ 400 MHzδ_(H)=12.55 (br s, 1H), 8.10 (d, 2H), 7.78-7.66 (m, 2H), 7.46 (d, 2H).

To a solution of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg,0.34 mmol) in THF (5 mL) was added tetrahydropyran-4-ylmethanol (117.65mg, 1.01 mmol), PPh₃ (177.1 mg, 0.68 mmol) and then DIAD (136.54 mg,0.68 mmol). The resulting mixture was stirred at 25° C. under N₂ for 16hours to give a solution. The reaction solution was concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to give theproduct (42.79 mg, 0.11 mmol,) as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=8.00 (d, 2H), 7.48 (s, 2H), 7.33 (d, 2H), 4.00 (dd, 2H), 3.92 (d,2H), 3.40 (t, 2H), 2.35-2.23 (m, 1H), 1.71-1.63 (m, 2H), 1.56-1.48 (m,2H). LCMS R_(t)=1.28 min in 2.0 min chromatography, MS ESI calcd. forC₁₉H₁₈F₃N₂O₄ [M+H]⁺395.1, found 395.0.

Example 81. Synthesis of Compound 102

To a solution of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg,0.34 mmol) in THF (5 mL) was added oxetan-3-ylmethanol (89.24 mg, 1.01mmol), PPh₃ (177.1 mg, 0.68 mmol) and then DIAD (136.54 mg, 0.68 mmol).The resulting mixture was stirred at 25° C. under N₂ for 16 hours togive a solution. The reaction solution was concentrated to give thecrude product. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 10% to 20%) to give the product (84.3 mg,0.23 mmol, 68% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=7.99 (d,2H), 7.49 (s, 2H), 7.33 (d, 2H), 4.90-4.84 (m, 2H), 4.71 (t, 2H), 4.34(d, 2H), 3.66-3.54 (m, 1H). LCMS R_(t)=1.22 min in 2.0 minchromatography, MS ESI calcd. for C₁₇H₁₄F₃N₂O₄ [M+H]⁺ 367.1, found367.0.

Example 82. Synthesis of Compound 103

To a solution of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg,0.34 mmol) in THF (5 mL) was added pyrimidin-5-ylmethanol (111.52 mg,1.01 mmol), PPh₃ (177.1 mg, 0.68 mmol) and then DIAD (136.54 mg, 0.68mmol). The resulting mixture was stirred at 25° C. under N₂ for 16 hoursto give a solution. The reaction solution was concentrated to give thecrude product. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 10% to 20%) to give the product (98.9 mg,0.25 mmol, 75% yield) as a solid. ¹H NMR DMSO-d₆ 400 MHz δ_(H)=9.14 (s,1H), 8.96 (s, 2H), 8.16 (d, 2H), 7.85-7.78 (m, 2H), 7.48 (d, 2H), 5.17(s, 2H). LCMS R_(t)=1.17 min in 2.0 min chromatography, MS ESI calcd.for C₁₈H₁₂F₃N₄O₃ [M+H]⁺ 389.1, found 389.0.

Example 83. Synthesis of Compound 104

To a solution of (2S)-tetrahydrofuran-2-carboxylic acid (2 g, 17.22mmol) in THF (3 mL) was added the BH₃.SMe₂ (2.58 mL, 25.84 mmol) at 0°C., then the mixture was stirred at 20° C. for 16 hours to give acolorless solution. 2N NaOH (10 mL) was added to the mixture slowly at0° C. Then the mixture was extracted with EtOAc (20 mL×2). The combinedorganic phase was washed with brine (10 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product (400 mg, 3.92 mmol, 23%yield) as colorless oil. ¹H NMR CDCl₃, 400 MHz δ_(H)=4.06-3.99 (m, 1H),3.92-3.84 (m, 1H), 3.83-3.75 (m, 1H), 3.73-3.62 (m, 1H), 3.57-3.45 (m,1H), 2.13-2.05 (m, 1H), 1.98-1.87 (m, 3H), 1.70-1.59 (m, 1H).

To the mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one(100.00 mg, 0.34 mmol), [(2S)-tetrahydrofuran-2-yl]methanol (103.79 mg,1.02 mmol) and PPh₃ (177.70 mg, 0.68 mmol) in THF (5.00 mL) was addedthe DIAD (136.99 mg, 0.68 mmol) at 0° C. and the mixture was stirredunder N₂ at 20° C. for 16 hours to give a mixture. The mixture wasdiluted with H₂O (20 mL), extracted with EtOAc (20 mL×2). The combinedorganic phase was washed with brine (10 mL), dried over Na₂SO₄, filteredand the filtrate was concentrated to give the crude product. The crudeproduct was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 □m),A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 60-90% B over 6.6 minutes) to givethe product (40.86 mg, 0.11 mmol, 32% yield) as oil.

Note: the Specific rotation was +19.79 (c=1, CHCl₃, 27.5° C.). ¹H NMRDMSO-d₆ 400 MHz δ_(H)=7.80 (d, 2H), 7.66 (s, 1H), 7.47 (d, 2H), 7.43 (s,2H), 4.30-4.20 (m, 1H), 3.97-3.87 (m, 2H), 3.78-3.70 (m, 1H), 3.66-3.59(m, 1H), 2.08-1.75 (m, 3H), 1.71-1.59 (m, 1H). LCMS R_(t)=1.48 min in2.0 min chromatography, MS ESI calcd. for C₁₉H₁₇F₃NO₄ [M+H]⁺ 380.1,found 380.1.

Example 84. Synthesis of Compound 105

To a solution of (2R)-tetrahydrofuran-2-carboxylic acid (2 g, 17.22mmol) in THF (20 mL) was added the BH₃.SMe₂ (2.58 mL, 25.84 mmol) at 0°C., then the mixture was stirred at 20° C. for 16 hours to give thecolorless solution. 2N NaOH (10 mL) was added to the mixture slowly at0° C. Then the mixture was extracted with EtOAc (20 mL×2). The combinedorganic phase was washed with brine (10 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product (450.00 mg, 4.41 mmol, 26%yield) as colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=4.07-3.97 (m,1H), 3.94-3.85 (m, 1H), 3.84-3.76 (m, 1H), 3.72-3.63 (m, 1H), 3.55-3.46(m, 1H), 2.02-1.87 (m, 4H), 1.72-1.65 (m, 1H).

To the mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one(150.00 mg, 0.51 mmol), [(2R)-tetrahydrofuran-2-yl]methanol (155.68 mg,1.52 mmol) and PPh₃ (266.55 mg, 1.02 mmol) in THF (5 mL) was added theDIAD (205.49 mg, 1.02 mmol) at 0° C. and the mixture was stirred underN₂ at 20° C. for 16 hours to give the mixture. The mixture was dilutedwith H₂O (20 mL), and the mixture was extracted with EtOAc (20 mL×2).The combined organic phase was washed with brine (10 mL), dried overNa₂SO₄, filtered and the filtrate was concentrated to give the crudeproduct. The crude product was purified by Prep-HPLC (Waters Xbridge(150 mm×25 mm, 5 μm), A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 56-86% B over 6minutes) to give the product (28.34 mg, 0.07 mmol, 15% yield) as oil.

Note: the Specific rotation was −14.51 (c=1, CHCl₃, 27.7° C.). ¹H NMRDMSO-d₆ 400 MHz δ_(H)=7.80 (d, 2H), 7.66 (s, 1H), 7.47 (d, 2H), 7.43 (s,2H), 4.29-4.21 (m, 1H), 3.98-3.87 (m, 2H), 3.79-3.71 (m, 1H), 3.67-3.58(m, 1H), 2.08-1.74 (m, 3H), 1.70-1.60 (m, 1H). LCMS R_(t)=1.35 min in2.0 min chromatography, MS ESI calcd. for C₁₉H₁₇F₃NO₄ [M+H]⁺ 380.1,found 379.8.

Example 85. Synthesis of Compounds 53, 106, and 107

To a solution of 2,2-difluorocyclopropanecarboxylic acid (1 g, 8.19mmol) in Ether (30 mL) was added LiA1H₄ (466.33 mg, 12.29 mmol) slowlyat 0° C. over 10 mins. After the addition, the resulting colorlesssuspension was allowed to warm to 25° C., and stirred for a further 18hours to give a suspension. The reaction mixture was then cooled in anice-bath, and then 2M NaOH (1 mL) was added in a dropwise manner toquench the reaction, followed by H₂O (1 mL). The mixture was filtered,and rinsed with Et₂O (10 mL×2). The filtrate was concentrated to give aresidue. Then the residue was re-dissolved in DCM (20 mL), dried overanhydrous MgSO₄ and filtered. The filtrate was concentrated at 5-10° C.to give the crude product (800 mg, 7.40 mmol, 90% yield) as oil. ¹H NMR(CDCl₃, 400 MHz) δ_(H)=3.82-3.74 (m, 1H), 3.71-3.63 (m, 1H), 1.98-1.76(m, 1H), 1.53-1.41 (m, 1H), 1.22-1.11 (m, 1H).

To a solution of (2,2-difluorocyclopropyl)methanol (232 mg, 2.15 mmol)and 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (200mg, 0.68 mmol) in THF (4 mL) was added PPh₃ (354.21 mg, 1.35 mmol) andDIAD (273.07 mg, 1.35 mmol). The resulting mixture was stirred at 20° C.under N₂ for 16 hours to give a solution. The reaction solution wasconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) togive compound 53 (150 mg) as a solid.

Compound 53 ¹H NMR (CDCl₃+D₂O 400 MHz) δ_(H)=8.00 (d, 2H), 7.51 (s, 2H),7.33 (d, 2H), 4.31-4.22 (m, 1H), 4.09-4.00 (m, 1H), 2.35-2.21 (m, 1H),1.61 (m, 2H). LCMS R_(t)=1.31 min using Method A, MS ESI calcd. forC₁₇H₁₂F₅N₂O₃ [M+H]⁺ 387.1, found 387.0.

The product was purified by SFC (Column: OJ (250 mm×30 mm, 5 μm); A=CO₂and B=Neu-ETOH; 35° C.; 50 mL/min; 20% B; 10 min run; 13 injections, Rtof Peak 1=7.7 min, Rt of Peak 2=8.5 min) to give the compound 106 (24.52mg, 0.06 mmol) (Peak 1, R_(t)=2.749 min in SFC) as a solid and compound107 (Peak 2, R_(t)=2.959 min in SFC) (˜80 mg, ee %=80%).

The impure compound 107 was purified again by SFC (Column: OJ (250 mm×30mm, 5 μm); A=CO₂ and B=0.1%NH₃H₂O ETOH; 35° C.; 50 mL/min; 25% B; 9 minrun; 8 injections, Rt of Peak 1=7.17 min, Rt of Peak 2=7.8 min) to givethe product of3-[[(1S)-2,2-difluorocyclopropyl]methyl]-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-2-one(39.28 mg, 0.10 mmol, 14.95% yield, 99.29% purity) (Peak 2, R_(t)=2.959min in SFC) as a solid.

Compound 106: ¹H NMR CDCl₃+D₂O 400 MHz δ=8.00 (d, 2H), 7.51 (s, 2H),7.33 (d, 2H), 4.26 (dd, 1H), 4.04 (dd, 1H), 2.36-2.20 (m, 1H), 1.62-1.46(m, 2H). LCMS R_(t)=1.27 min in 2.0 min chromatography, MS ESI calcd.for C₁₇H₁₂F₅N₂O₃ [M+H]⁺ 387.1, found 387.0.

Compound 107: ¹H NMR CDCl₃ +D₂O 400 MHz 6=8.00 (d, 2H), 7.51 (s, 2H),7.33 (d, 2H), 4.26 (dd, 1H), 4.04 (dd, 1H), 2.36-2.19 (m, 1H), 1.62-1.46(m, 2H). LCMS R_(t)=1.32 min in 2.0 min chromatography, MS ESI calcd.for C₁₇H₁₂F₅N₂O₃ [M+H]⁺ 387.1, found 387.0.

Example 86. Synthesis of Compound 108

A mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (300mg, 1.02 mmol), tert-butyl(3S)-3-(hydroxymethyl)pyrrolidine-l-carboxylate (409.05 mg, 2.03 mmol),PPh₃ (533.09 mg, 2.03 mmol) and DIAD (410.98 mg, 2.03 mmol) in THF (20mL) was stirred at 20° C. under N₂ for 16 hours. The mixture wasconcentranted and purified by flash chromatography on silica gel (EtOAcin PE=10% to 25%) to afford the product (430 mg, 0.90 mmol, 88% yield)as an oil. LCMS R_(t)=0.95 min in 1.5 min chromatography, MS ESI calcd.for C₂₄H₂₅F₃N₂O₅Na [M+Na]⁺ 501.2, found 501.2.

A mixture oftert-butyl(3S)-3-[[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazolyl]methyl]pyrrolidine-1-carboxylate (430 mg, 0.90 mmol) in 4 MHCl/dioxane (10 mL, 0.90 mmol) was stirred at 20° C. for 16 hours. Themixture was concentrated to afford the crude product (400 mg, 0.96 mmol)as oil. LCMS R_(t)=0.75 min in 1.5 min chromatography, MS ESI calcd. forC₁₉H₁₈F₃N₂O₃ [M+H]⁺ 379.1, found 379.0.

A mixture of3-[[(3S)-pyrrolidin-3-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-onehydrochloride (100 mg, 0.24 mmol), acetyl chloride (37.85 mg, 0.48 mmol)and Et₃N (0.17 mL, 1.21 mmol) in CH₂Cl₂ (20 mL) was stirred at 20° C.for 16 h. The reaction mixture was concentrated and purified byprep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H₂O (10 mM NH₄HCO₃)and B=CH₃CN; 45-75% B over 6 minutes) to give the product (35.75 mg,0.09 mmol, 35% yield, 100%) as a solid. ¹H NMR (MeOD-d₄ 400 MHz)δ_(H)=7.74 (d, 2H), 7.51 (dd, 1H), 7.46-7.40 (m, 1H), 7.39-7.32 (m, 3H),3.99 (dd, 2H), 3.75-3.33 (m, 4H), 2.97-2.78 (m, 1H), 2.23-2.08 (m, 1H),2.06-2.01 (m, 3H), 1.98-1.75 (m, 1H). LCMS R_(t)=1.19 min in 2.0 minchromatography, MS ESI calcd. for C₂₁H₂₀F₃N₂O₄ [M+H]⁺ 421.1, found421.1.

Example 87. Synthesis of Compound 109

A mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (300mg, 1.02 mmol), tert-butyl(2R)-2-(hydroxymethyl)pyrrolidine-l-carboxylate (409.05 mg, 2.03 mmol),PPh₃ (533.09 mg, 2.03 mmol) and DIAD (410.98 mg, 2.03 mmol) in THF (20mL) was stirred at 20° C. under N₂ for 16 hours. The mixture wasconcentrated and purified by flash chromatography on silica gel (EtOAcin PE=10% to 25%) to afford the product (330 mg, 0.69 mmol, 68% yield)as an oil. LCMS R_(t)=1.16 min in 1.5 min chromatography, MS ESI calcd.for C₂₄H₂₅F₃N₂O₅Na [M+Na]⁺ 501.2, found 501.2.

A mixture oftert-butyl(2R)-2-[[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-3-yl]methyl]pyrrolidine-1-carboxylate(330 mg, 0.69 mmol) in 4M HCl/dioxane (10 mL, 0.69 mmol) was stirred at20° C. for 16 hours. The mixture was concentrated to give the product(280 mg, 0.67 mmol, 98% yield) as a solid. LCMS R_(t)=0.76 min in 1.5min chromatography, MS ESI calcd. for C₁₉H₁₈F₃N₂O₃ [M+H]⁺ 379.1, found379.0.

A mixture of3-[[(2R)-pyrrolidin-2-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-onehydrochloride (100 mg, 0.24 mmol), acetyl chloride (37.85 mg, 0.48 mmol)and Et₃N (0.17 mL, 1.21 mmol) in DCM (25 mL) was stirred at 20° C. for16 hours. The mixture was concentrated and purified by Prep-HPLC (WatersXbridge (150 mm×25 mm, 5 μm), A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 47-77%B over 6 minutes) to give the product (47.32 mg, 0.11 mmol, 46% yield)as a solid. ¹H NMR (MeOD, 400 MHz) δ_(H)=7.79-7.66 (m, 3H), 7.45-7.30(m, 4H), 4.57-4.47 (m, 1H), 4.08-3.93 (m, 2H), 3.65-3.56 (m, 1H),3.54-3.45 (m, 1H), 2.18-1.94 (m, 7H). LCMS R_(t)=1.23 min in 2.0 minchromatography, MS ESI calcd. for C₂₁H₂₀F₃N₂O₄ [M+H]⁺ 421.1, found421.1.

Example 88. Synthesis of Compound 110

A mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (300mg, 1.02 mmol), tert-butyl(3R)-3-(hydroxymethyl)pyrrolidine-l-carboxylate (409.05 mg, 2.03 mmol),PPh₃ (533.09 mg, 2.03 mmol) and DIAD (410.98 mg, 2.03 mmol) in THF (20mL) was stirred at 20° C. under N₂ for 16 hours. The reaction wasdiluted with sat.NH₄Cl (20 mL), and the mixture was extracted with EtOAc(10 mL×2). The combined organic phase was washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated to give the crude product.The crude product was purified by flash chromatography on silica gel(EtOAc in PE=10% to 25%) to give the impure product (600 mg, 1.25 mmol)as oil. LCMS R_(t)=0.96 min in 1.5 min chromatography, MS ESI calcd. forC₂₄H₂₅F₃N₂O₅Na [M+Na]⁺ 501.2, found 501.1.

A mixture of tert-butyl(3R)-3-[[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-3-yl]methyl]pyrrolidine-1-carboxylate(600 mg, 1.25 mmol) in 4M HCl/dioxane (10 mL) was stirred at 20° C. for16 hours. The mixture was concentrated to give the crude product (600mg, 1.45 mmol) as oil. The product was used directly without any furtherpurification. LCMS R_(t)=0.75 min in 1.5 min chromatography, MS ESIcalcd. for C₁₉H₁₈F₃N203 [M+H]⁺ 379.1, found 379.0.

A mixture of3-[[(3R)-pyrrolidin-3-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-onehydrochloride (100 mg, 0.24 mmol), acetyl chloride (37.85 mg, 0.48 mmol)and Et₃N (0.17 mL, 1.21 mmol) in DCM (20 mL) was stirred at 20° C. for16 hours to give a mixture. From LCMS, desired MS was observed, and nostarting material was remained. The reaction was diluted with sat.NH₄Cl(20 mL), and the mixture was extracted with DCM (15 mL×2). The combinedorganic phase was washed with brine (10 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by Prep-HPLC (Waters Xbridge (150 mm×25 mm 5 μm), A=H₂O (10 mMNH₄HCO₃) and B=CH₃CN, 45%-55% B over 8 minutes) to give the impureproduct. The impure product was purified by Prep-TLC (silica gel,PE:EtOAc=1:1) to give the product (11.95 mg, 0.03 mmol, 12% yield) as asolid. ¹H NMR DMSO-d₆ 400 MHz δ_(H)=7.74 (d, 2H), 7.53-7.48 (m, 1H),7.45-7.40 (m, 1H), 7.39-7.31 (m, 3H), 3.98 (dd, 2H), 3.73-3.32 (m, 4H),2.97-2.79 (m, 1H), 2.19-2.07 (m, 1H), 2.05-2.00 (m, 3H), 1.96-1.77 (m,1H). LCMS R_(t)=1.22 min in 2 min chromatography, MS ESI calcd. forC₂₁H₂₀F₃N₂O₄ [M+H]⁺ 421.1, found 421.1.

Example 89. Synthesis of Compound 111

A mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (300mg, 1.02 mmol), tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-l-carboxylate (409.05 mg, 2.03 mmol),PPh₃ (533.09 mg, 2.03 mmol) and DIAD (410.98 mg, 2.03 mmol) in THF (20mL) was stirred at 25° C. under N₂ for 16 hours. The reaction wasquenched with sat.NH₄Cl (20 mL), and the mixture was extracted withEtOAc (10 mL×2). The combined organic phase was washed with brine (10mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=10% to 25%) to afford the crude product (400 mg,0.84 mmol, 83% yield) as oil. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=7.62-7.39(m, 3H), 7.22-6.98 (m, 4H), 4.25-4.15 (m, 1H), 3.98-3.79 (m, 2H),3.43-3.18 (m, 2H), 1.95-1.77 (m, 4H), 1.30 (s, 9H).

A mixture oftert-butyl(2S)-2-[[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-3-yl]methyl]pyrrolidine-1-carboxylate(400 mg, 0.84 mmol) in 4 M HCl/dioxane (10 mL) was stirred at 25° C. for16 hours. The mixture was concentrated to afford the crude product (300mg, 0.68 mmol, 82% yield) as oil. LCMS R_(t)=0.75 min in 1.5 minchromatography, MS ESI calcd. for C₁₉H₁₈F₃N₂O₃ [M+H]⁺ 379.1, found379.0.

A mixture of3-[[(2S)-pyrrolidin-2-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-onehydrochloride (100 mg, 0.24 mmol), acetyl chloride (37.85 mg, 0.48 mmol)and Et₃N (0.17 mL, 1.21 mmol) in CH₂Cl₂(20 mL) was stirred at 25° C. for16 hours to give a solution. The reaction was quenched with sat.NH₄Cl(20 mL), and the mixture was extracted with CH₂Cl₂ (10 mL×2). Thecombined organic phase was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=30% to80%) to give impure product. The impure product was purified byPrep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H₂O (10 mM NH₄HCO₃),and B=CH₃CN; 47-77% B over 6 minutes) to give the product (12.41 mg,0.03 mmol, 12% yield) as a solid. ¹H NMR MeOD-d₄ 400 MHz δ_(H)=7.79-7.67(m, 3H), 7.47-7.30 (m, 4H), 4.57-4.46 (m, 1H), 4.08-3.91 (m, 2H),3.64-3.44 (m, 2H), 2.20-1.93 (m, 7H). LCMS R_(t)=1.25 min in 2.0 minchromatography, MS ESI calcd. for C₂₁H₂₀F₃N₂O₄ [M+H]⁺ 421.1, found421.1.

Example 90. Synthesis of Compound 112

A mixture of3-[[(2S)-pyrrolidin-2-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-onehydrochloride (100 mg, 0.24 mmol), Et₃N (0.17 mL, 1.21 mmol) and methylcarbonochloridate (45.56 mg, 0.48 mmol) in CH₂Cl₂ (10 mL) was stirred at25° C. for 16 hours. The reaction was quenched with sat NH₄Cl (10 mL),and the mixture was extracted with CH₂Cl₂ (10 mL×2). The combinedorganic phase was washed with brine (10 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H₂O (10 mMNH₄HCO₃) and B=CH₃CN; 57-77% B over 6 minutes) to give the product(71.61 mg, 0.16 mmol, 68% yield) as a solid. ¹H NMR DMSO-d6 +D20 400 MHzδ_(H)=7.80-7.71 (m, 2H), 7.59-7.38 (m, 5H), 4.30-4.17 (m, 1H), 3.99-3.83(m, 2H), 3.40-3.17 (m, 5H), 2.02-1.73 (m, 4H). LCMS R_(t)=1.30 min in2.0 min chromatography, MS ESI calcd. for C₂₁H₂₀F₃N₂O₅ [M+H]⁺ 437.1,found 437.0.

Example 91. Synthesis of Compound 113

A mixture of3-[[(2S)-pyrrolidin-2-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-onehydrochloride (100 mg, 0.24 mmol), Et₃N (0.17 mL, 1.21 mmol) andmethanesulfonyl chloride (55.23 mg, 0.48 mmol) in CH₂Cl₂ (10 mL) wasstirred at 25° C. for 16 hours. The reaction was quenched with sat.NH₄Cl(10 mL), and the mixture was extracted with CH₂Cl₂ (10 mL×2). Thecombined organic phase was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 um), A=H₂O(10 mM NH₄HCO₃) and B=CH₃CN; 55-75% B over 6 minutes) to give theproduct (47.27 mg, 0.10 mmol, 43% yield) as a solid. ¹H NMR DMSO-d₆+D₂O400 MHz δ_(H)=7.78 (d, 2H), 7.61 (s, 1H), 7.48-7.38 (m, 4H), 4.13-4.07(m, 1H), 3.97-3.86 (m, 2H), 3.31-3.20 (m, 2H), 2.86 (s, 3H), 2.05-1.79(m, 4H). LCMS R_(t)=1.26 min in 2.0 min chromatography, MS ESI calcd.for C₂₀H₂₀F₃N₂O₅S [M+H]⁺ 457.1, found 457.0.

Example 92. Synthesis of Compound 114

To the mixture of2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-3-yl]acetic acid(500 mg, 1.42 mmol), (3R)-pyrrolidin-3-ol (184.97 mg, 2.12 mmol) andHATU (1.61 g, 4.25 mmol) in DMF (10 mL) was added the DIPEA (0.74 mL,4.25 mmol). And the mixture was stirred at 25° C. for 16 hours. Themixture was diluted with H₂O (10 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with brine (10mL), dried over Na₂SO₄ and filtered. The filtrate was concentrated togive the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=20% to 50% to 100%) to givethe impure product (300 mg, ˜50% yield) as a solid.

A part of the impure product (100 mg) was triturated from i-Pr₂O (2 mL)to give the product (55 mg, 0.13 mmol, 55% yield) as a solid. ¹H NMRDMSO-d6+D20 400 MHz δ_(H)=7.72 (d, 2H), 7.49-7.37 (m, 5H), 4.79-4.61 (m,2H), 4.43-4.25 (m, 1H), 3.69-3.23 (m, 4H), 2.09-1.70 (m, 2H). LCMSR_(t)=1.17 min in 2.0 min chromatography, MS ESI calcd. for C₂₀H₁₈F₃N205[M+H]⁺ 423.1, found 423.1.

Example 93. Synthesis of Compound 115

To the mixture of2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-3-yl]acetic acid(500 mg, 1.42 mmol), (3S)-pyrrolidin-3-ol (184.97 mg, 2.12 mmol) andHATU (1.61 g, 4.25 mmol) in DMF (10 mL) was added the DIPEA (0.74 mL,4.25 mmol). The mixture was stirred at 25° C. for 16 hours to give thesolution. The mixture was diluted with H₂O (20 mL), and the mixture wasextracted with EtOAc (20 mL×2). The combined organic phase was washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=20% to 50% to 100%) to givethe impure product (300 mg, ˜50% yield) as a solid.

The impure product (100 mg) was purified by Prep-HPLC (Xtimate C18 (150mm×25 mm 5 μm), A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 35-65% B over 9minutes) to give the product (43.95 mg, 0.10 mmol, 44% yield) as asolid. ¹H NMR DMSO-d₆+D₂O 400 MHz δ_(H)=7.72 (d, 2H), 7.54-7.34 (m, 5H),4.80-4.60 (m, 2H), 4.41-4.26 (m, 1H), 3.71-3.24 (m, 4H), 2.07-1.72 (m,2H). LCMS R_(t)=1.22 min in 2.0 min chromatography, MS ESI calcd. forC₂₀H₁₈F₃N₂O₅ [M+H]⁺ 423.1, found 423.1.

Example 94. Synthesis of Compound 116

A mixture of3-[[(2R)-pyrrolidin-2-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-onehydrochloride (90 mg, 0.22 mmol), Et₃N (0.15 mL, 1.08 mmol) and methylcarbonochloridate (41.01 mg, 0.43 mmol) in DCM (25 mL) was stirred at20° C. for 16 hours. The reaction was diluted with sat.NH₄Cl (15 mL),extracted with DCM (10 mL×2). The combined organic phase was washed withbrine (10 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by Prep-HPLC (WatersXbridge (150 mm×25 mm, 5 μm), A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 59-79%B over 6 minutes) to give the product (38.68 mg, 0.09 mmol, 41% yield)as a solid. ¹H NMR DMSO-d₆+D₂O 400 MHz δ_(H)=7.81-7.70 (m, 2H),7.55-7.34 (m, 5H), 4.29-4.16 (m, 1H), 3.97-3.85 (m, 2H), 3.41-3.13 (m,5H), 2.02-1.70 (m, 4H). LCMS R_(t)=1.30 min in 2 min chromatography, MSESI calcd. for C₂₁H₂₀F₃N₂O₅ [M+H]⁺ 437.1, found 437.1.

Example 95. Synthesis of Compound 117

To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one(100 mg, 0.34 mmol), 2-pyrimidin-5-ylethanol (126.15 mg, 1.02 mmol) andPPh₃ (177.7 mg, 0.68 mmol) in THF (6 mL) was added DIAD (136.99 mg, 0.68mmol) and the mixture was stirred under N₂ at 20° C. for 16 hours togive a mixture. The mixture was concentrated to dryness, diluted withH₂O (10 mL), and extracted with EtOAc (10 mL×2). The combined organicphase was washed with brine (10 mL), dried over Na₂SO₄, filtered. Andthe filtrate was concentrated to give the crude product. The crudeproduct was purified by Prep-HPLC (Kromasil (150 mm×25 mm, 10 μm), A=H₂O(0.05% NH₃ H₂O) and B=CH₃CN; 48-78% B over 7 minutes) to give theproduct (49.53 mg, 123.4 μmol, 36% yield) as a solid. ¹H NMR DMSO-d₆ 400MHz δ_(H)=9.02 (s, 1H), 8.73 (s, 2H), 7.78 (d, 2H), 7.60 (s, 1H), 7.48(d, 2H), 7.42 (s, 2H), 4.20 (t, 2H), 3.11 (t, 2H). LCMS R_(t)=1.17 minin 2 min chromatography, MS ESI calcd. for C₂oH₁₅F₃N₃O₃ [M+H]⁺ 402.1,found 402.1.

Example 96. Synthesis of Compound 118

A mixture of3-[[(2R)-pyrrolidin-2-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-onehydrochloride (100 mg, 0.24 mmol), Et₃N (0.17 mL, 1.21 mmol) andmethanesulfonyl chloride (55.23 mg, 0.48 mmol) in DCM (25 mL) wasstirred at 20° C. for 16 hours. The reaction was diluted with sat.NH₄Cl(15 mL), and extracted with DCM (10 mL×2). The combined organic phasewas washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H₂O (10 mM NH₄HCO₃)and B=CH₃CN; 55-75% B over 6 minutes) to give the product (22.24 mg,48.7 μmol, 20% yield, 100%) as a solid. ¹H NMR DMSO-d₆+D2O 400 MHzδ_(H)=7.77 (d, 2H), 7.59 (s, 1H), 7.46-7.34 (m, 4H), 4.13-4.07 (m, 1H),3.98-3.86 (m, 2H), 3.31-3.17 (m, 2H), 2.83 (s, 3H), 2.04-1.78 (m, 4H).LCMS R_(t)=1.25 min in 2 min chromatography, MS ESI calcd. forC₂₀H₂₀F₃N₂O₅S [M+H]⁺ 457.1, found 457.1.

Example 97. Synthesis of Compound 119

To a solution of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (500 mg,1.69 mmol) in THF (20 mL) was added tert-butyl 2-hydroxyacetate (669.28mg, 5.06 mmol), PPh₃ (885.52 mg, 3.38 mmol) and DIAD (682.68 mg, 3.38mmol). The resulting mixture was stirred at 25° C. under N₂ for 16 hoursto give a solution. The reaction solution was concentrated to give thecrude product. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 10% to 20%) to give the product (680 mg,1.66 mmol, 98% yield) as a solid. ¹H NMR CDCl₃, 400 MHz δ_(H)=7.97 (d,2H), 7.49 (s, 2H), 7.30 (d, 2H), 4.62 (s, 2H), 1.49 (s, 9H).

To a solution of tert-butyl2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]acetate(690 mg, 1.68 mmol) in DCM (10 mL) was added TFA (5.11 mL). Theresulting mixture was stirred at 25° C. for 3 hours to give a solution.The reaction solution was concentrated to give the crude product (586mg, 1.65 mmol, 98% yield) as a solid. ¹H NMR DMSO-d₆ 400 MHz δ_(H)=8.17(d, 2H), 7.92-7.79 (m, 2H), 7.48 (d, 2H), 4.67 (s, 2H).

To a solution of2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]aceticacid (195 mg, 0.55 mmol) in DMF (5 mL) was added HATU (313.96 mg, 0.83mmol), DIPEA (0.48 mL, 2.75 mmol) and then piperidine (56.25 mg, 0.66mmol). The resulting mixture was stirred at 25° C. for 16 hours to givea solution. Saturated NH₄Cl aqueous (20 mL) and EtOAc (20 mL) were addedto the reaction mixture and stirred for 5 minutes. After separated, theorganic layer was washed with water (20 mL×2), brine (20 mL×2), driedover anhydrous Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by Prep-TLC (silica gel,PE:EtOAc=1:1) to give the product (120.57 mg, 0.28 mmol, 52% yield) as asolid. ¹H NMR DMSO-d₆ 400 MHz δ_(H)=8.15 (d, 2H), 7.88 (d, 1H), 7.80 (d,1H), 7.49 (d, 2H), 4.86 (s, 2H), 3.59-3.51 (m, 2H), 3.46-3.41 (m, 2H),1.67-1.58 (m, 4H), 1.50-1.42 (m, 2H). LCMS R_(t)=1.21 min in 2.0 minchromatography, MS ESI calcd. for C₂₀H₁₉F₃N₃O₄ [M+H]⁺ 422.1, found422.1.

Example 98. Synthesis of Compound 120

To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one(100 mg, 0.34 mmol), 2-pyrazin-2-ylethanol (126.15 mg, 1.02 mmol) andPPh₃ (177.7 mg, 0.68 mmol) in THF (6 mL) was added the DIAD (136.99 mg,0.68 mmol), and the mixture was stirred under N₂ at 20° C. for 16 hoursto give the mixture. The mixture was concentrated to dryness, dilutedwith H₂O (10 mL), and the mixture was extracted with EtOAc (10 mL×2).The combined organic phase was washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated to give the crude product. The crudeproduct was purified by Prep-HPLC (Kromasil (150 mm×25 mm 10 μm), A=H₂O(0.05% NH₃.H₂O) and B=CH₃CN; 50-80% B over 7 minutes) to give theproduct (41.28 mg, 102.9 μmol, 30% yield) as a solid. ¹H NMR DMSO-d₆ 400MHz δ_(H)=8.64 (d, 1H), 8.52-8.49 (m, 1H), 8.47 (d, 1H), 7.77 (d, 2H),7.54 (s, 1H), 7.48 (d, 2H), 7.41 (s, 2H), 4.28 (t, 2H), 3.26 (t, 2H).LCMS R_(t)=1.19 min in 2 min chromatography, MS ESI calcd. forC₂₀H₁₅F₃N₃O₃ [M+H]⁺ 402.1, found 402.0.

Example 99. Synthesis of Compound 121

A mixture of 6-bromo-2-nitro-pyridin-3-ol (3 g, 13.7 mmol), Fe (7657.88mg, 136.99 mmol) and NH₄C1 (7329.1 mg, 136.99 mmol) in Ethanol (100 mL)and Water (100 mL) was stirred at 75° C. for 2 hours to give a blacksuspension. The reaction mixture was cooled to room temperature andfiltered through Celite. The filtrate was concentrated to give the crudeproduct (2.5 g, 13.22 mmol, 96.55% yield) as a solid. ¹H NMR DMSO-d₆ 400MHz δ_(H)=9.71 (s, 1H), 6.74 (d, 1H), 6.50 (d, 1H), 5.92 (br s, 2H).

A mixture of 2-amino-6-bromo-pyridin-3-ol (2.5 g, 13.23 mmol) and CDI(2.24 g, 15.87 mmol) in THF (100 mL) was stirred at 55° C. for 16 hours.The reaction solution was cooled to room temperature and concentrated togive the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=10% to 30% to 50%) to give theproduct (900 mg, 4.18 mmol, 32% yield) as a solid. ¹H NMR DMSO-d₆ 400MHz δ_(H)=12.68 (s, 1H), 7.62 (d, 1H), 7.33 (d, 1H).

To a solution of 5-bromo-3H-oxazolo[4,5-b]pyridin-2-one (200 mg, 0.93mmol) in THF (10 mL) was added PPh₃ (487.98 mg, 1.86 mmol),2-pyrimidin-2-ylethanol (230.96 mg, 1.86 mmol) and then DIAD (376.2 mg,1.86 mmol). The resulting mixture was stirred at 25° C. under N₂ for 16hours. The reaction solution was concentrated to give a residue. Water(20 mL) was added to the residue, and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with brine (20mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=10% to 30% to 50%) to give theproduct (200 mg, 0.62 mmol, 67% yield) as a solid. ¹H NMR (CDCl₃, 400MHz) δ_(H)=8.63 (d, 2H), 7.25-7.15 (m, 3H), 4.44 (t, 2H), 3.48 (t, 2H).

A mixture of5-bromo-3-(2-pyrimidin-2-ylethyl)oxazolo[4,5-b]pyridin-2-one (60 mg,0.19 mmol),4,4,5,5-tetramethyl-2-[2-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane(67.73 mg, 0.22 mmol), K₃PO₄ (79.33 mg, 0.37 mmol) and Pd(t-Bu₃P)₂(14.32 mg, 0.03 mmol) in 1,4-Dioxane (4 mL) and Water (0.40 mL) wasstirred at 80° C. under N₂ for 16 hours to give a suspension. Thereaction mixture was cooled to room temperature and filtered throughCelite. The filtrate was concentrated to give the crude product. Thecrude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) togive the product (53.55 mg, 0.12 mmol, 68% yield) as a solid. ¹H NMR(CDCl₃, 400 MHz) δ_(H)=8.61 (d, 2H), 7.46 (d, 1H), 7.37 (d, 1H),7.15-7.08 (m, 4H), 4.49 (t, 2H), 3.51 (t, 2H), 2.38 (s, 3H). LCMSR_(t)=1.18 min in 2.0 min chromatography, MS ESI calcd. for C₂₀H₁₆F₃N₄O₃[M+H]⁺ 417.1, found 417.1.

Example 100. Synthesis of Compound 122

A mixture of5-bromo-3-(2-pyrimidin-2-ylethyl)oxazolo[4,5-b]pyridin-2-one (60 mg,0.19 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(71.99 mg, 0.22 mmol), K₃PO₄ (79.33 mg, 0.37 mmol) and Pd(t-Bu₃P)₂(14.32 mg, 0.03 mmol) in 1,4-Dioxane (4 mL) and Water (0.40 mL) wasstirred at 80° C. under N₂ for 16 hours to give a suspension. Thereaction mixture was cooled to room temperature and filtered throughCelite. The filtrate was concentrated to give the crude product. Thecrude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) togive the product (57.98 mg, 0.13 mmol, 71% yield) as a solid. ¹H NMR(CDCl₃, 400 MHz) δ_(H)=8.63 (d, 2H), 8.45 (d, 1H), 8.01 (dd, 1H),7.48-7.40 (m, 2H), 7.12 (t, 1H), 4.90 (q, 2H), 4.52 (t, 2H), 3.54 (t,2H). LCMS R_(t)=1.14 min in 2.0 min chromatography, MS ESI calcd. forC₁₉H₁₄F₄N₅O₃ [M+H]⁺ 436.1, found 436.0.

Example 101. Synthesis of Compound 123

To a mixture of5[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg,0.34 mmol), and 2-pyrazin-2-ylethanol (125.73 mg, 1.01 mmol) in THF (10mL) was added PPh₃ (177.1 mg, 0.68 mmol) and DIAD (136.54 mg, 0.68mmol). The reaction mixture was stirred at 20° C. under N₂ for 16 hours.After cooling to r.t., the mixture was diluted with H₂O (10 mL) andextracted with EtOAc (20 mL×2). The combined organic phase was washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=0 to 30%) to give the product(49.1 mg, 0.12 mmol, 36% yield) as a solid.

¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.50-8.46 (m, 2H), 8.39 (d, 1H), 7.94 (d,2H), 7.46 (s, 2H), 7.32 (d, 2H), 4.46 (t, 2H), 3.43 (t, 2H). LCMSR_(t)=1.37 min in 2.0 min chromatography, MS ESI calcd. for C₁₉H₁₄F₃N₄O₃[M+H]⁺ 403.1, found 403.0.

Example 102. Synthesis of Compound 124

To a mixture of5[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg,0.34 mmol), 2-pyrimidin-5-ylethanol (125.73 mg, 1.01 mmol) in THF (10mL) was added PPh₃ (177.1 mg, 0.68 mmol) and DIAD (136.54 mg, 0.68mmol). The reaction mixture was stirred at 20° C. under N₂ for 16 hours.After cooling to r.t., the mixture was diluted with H₂O (10 mL) andextracted with EtOAc (20 mL×2). The combined organic phase was washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=0 to 30%) to give the product(23.15 mg, 0.06 mmol, 17% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=9.08 (s, 1H), 8.68 (s, 2H), 7.95-7.90 (d, 2H), 7.48 (s, 2H), 7.34(d, 2H), 4.30 (t, 2H), 3.26 (t, 2H). LCMS R_(t)=1.24 min in 2.0 minchromatography, MS ESI calcd. for C₁₉H₁₄F₃N₄O₃ [M+H]⁺ 403.1, found402.8.

Example 103. Synthesis of Compound 125

To a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate(1000 mg, 5.34 mmol) in THF (20 mL) was added NaH (256.36 mg, 6.41mmol). The reaction mixture was stirred at 20° C. for 0.5 hour. Theniodomethane (1516.13 mg, 10.68 mmol) was added. The reaction mixture wasstirred at 20° C. for 2 hours to give a mixture. The reaction mixturewas diluted with sat.NH₄Cl (30 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with brine (15mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct (1100 mg, 5.47 mmol) as an oil. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=3.97-3.88 (m, 1H), 3.52-3.36 (m, 4H), 3.33 (s, 3H), 2.05-1.85 (m,2H), 1.46 (s, 9H).

A mixture of tert-butyl (3S)-3-methoxypyrrolidine-l-carboxylate (1100mg, 5.47 mmol) in 4M HCl/dioxane (15 mL, 60 mmol) was stirred at 20° C.for 16 hours to give a mixture. The reaction mixture was concentrated togive the crude product (1000 mg, 7.27 mmol) as an oil, which was useddirectly in next step. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=10.03-9.49 (m, 2H),4.13-4.06 (m, 1H), 3.53-3.34 (m, 4H), 3.32 (s, 3H), 2.26-2.13 (m, 1H),2.09-1.93 (m, 1H).

To the mixture of 2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazolyl]acetic acid (200 mg, 0.57 mmol), (3S)-3-methoxypyrrolidinehydrochloride (155.82 mg, 1.13 mmol) and HATU (645.83 mg, 1.7 mmol) inDMF (3 mL) was added the DIPEA (0.3 mL, 1.7 mmol). The mixture wasstirred at 25° C. for 16 hours to give the solution. The mixture wasdiluted with H₂O (10 mL), and the mixture was extracted with EtOAc (20mL×2). The combined organic phase was washed with brine (10 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product. Thecrude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) togive the impure product. The impure product was further purified bytriturating from i-Pr₂O (2 mL) to give the product (35.39 mg, 80.5 μmol,14% yield) as a solid. ¹H NMR DMSO-d₆+D₂O 400 MHz δ_(H)=7.71 (d, 2H),7.47-7.36 (m, 5H), 4.81-4.60 (m, 2H), 4.08-3.93 (m, 1H), 3.70-3.40 (m,3H), 3.34-3.17 (m, 4H), 2.13-1.82 (m, 2H). LCMS R_(t)=1.23 min in 2.0min chromatography, MS ESI calcd. for C₂₁H₂₀F₃N₂O₅ [M+H]⁺ 437.1, found436.8.

Example 104. Synthesis of Compound 126

To a solution of tert-butyl (3R)-3-hydroxypyrrolidine-l-carboxylate(1000 mg, 5.34 mmol) in THF (20 mL) was added NaH (256.36 mg, 6.41mmol). The reaction mixture was stirred at 20° C. for 0.5 hour. Theniodomethane (1516.13 mg, 10.68 mmol) was added. The reaction mixture wasstirred at 20° C. for 2 hours to give a mixture. The reaction mixturewas diluted with sat.NH₄Cl (30 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with brine (15mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct (1100 mg, 5.47 mmol) as an oil. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=3.97-3.88 (m, 1H), 3.53-3.36 (m, 4H), 3.33 (s, 3H), 2.06-1.84 (m,2H), 1.46 (s, 9H).

A mixture of tert-butyl (3R)-3-methoxypyrrolidine-l-carboxylate (1100mg, 5.47 mmol) in 4M HCl/dioxane (15 mL, 60 mmol) was stirred at 20° C.for 16 hours to give a mixture. The reaction mixture was concentrated togive the crude (1000 mg, 7.27 mmol) as an oil. ¹H NMR CDCl3, 400 MHzδ_(H)=10.10-9.39 (m, 2H), 4.13-4.04 (m, 1H), 3.51-3.35 (m, 4H), 3.31 (s,3H), 2.24-2.12 (m, 1H), 2.08-1.95 (m, 1H).

To the mixture of2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-3-yl]acetic acid(200 mg, 0.57 mmol), (3R)-3-methoxypyrrolidine hydrochloride (116.87 mg,0.85 mmol) and HATU (645.83 mg, 1.7 mmol) in DMF (3 mL) was added theDIPEA (0.3 mL, 1.7 mmol). And the mixture was stirred at 25° C. for 2hours to give the solution. The mixture was diluted with H₂O (10 mL),and the mixture was extracted with EtOAc (20 mL×2). The combined organicphase was washed with brine (10 mL), dried over Na₂SO₄, filtered. Thefiltrate was concentrated to give the crude product. The crude productwas purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the impureproduct. The impure product was further purified by triturating fromi-Pr₂O (2 mL) to give the product (81.18 mg, 0.18 mmol, 33% yield) as asolid. ¹H NMR DMSO-d₆+D₂O 400 MHz δ_(H)=7.69 (d, 2H), 7.43-7.35 (m, 5H),4.77-4.59 (m, 2H), 4.10-3.94 (m, 1H), 3.69-3.41 (m, 3H), 3.34-3.18 (m,4H), 2.13-1.83 (m, 2H). LCMS R_(t)=1.26 min in 2.0 min chromatography,MS ESI calcd. for C₂₁H₂₀F₃N₂O₅ [M+H]⁺ 437.1, found 436.8.

Example 105. Synthesis of Compound 127

A mixture of3-[[(3S)-pyrrolidin-3-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-onehydrochloride (150 mg, 0.40 mmol), Et₃N (0.27 mL, 1.98 mmol) and methylcarbonochloridate (74.93 mg, 0.79 mmol) in CH₂Cl₂ (10 mL) was stirred at25° C. for 16 hours to give a mixture. The reaction was quenched withsat.NH₄Cl (10 mL), and the mixture was extracted with CH₂Cl₂ (10 mL×2).The combined organic phase was washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated to give the crude product. The crudeproduct was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm),A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 55-75% B over 6 minutes) to give theproduct (58.59 mg, 0.13 mmol, 34% yield) as a solid.

¹H NMR DMSO-d₆ 400 MHz δ_(H)=7.81 (d, 2H), 7.71 (s, 1H), 7.51-7.41 (m,4H), 3.92 (d, 2H), 3.58-3.49 (m, 3H), 3.48-3.39 (m, 2H), 3.29-3.20 (m,1H), 3.16-3.09 (m, 1H), 2.82-2.69 (m, 1H), 2.03-1.91 (m, 1H), 1.78-1.62(m, 1H). LCMS R_(t)=1.40 min in 2.0 min chromatography, MS ESI calcd.for C₂₁H₂₀F₃N₂O₅ [M+H]⁺ 437.1, found 437.1.

Example 106. Synthesis of Compound 128

A mixture of3-[[(3S)-pyrrolidin-3-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-onehydrochloride (150 mg, 0.40 mmol), Et₃N (0.27 mL, 1.98 mmol) andmethanesulfonyl chloride (90.83 mg, 0.79 mmol) in CH₂Cl₂ (10 mL) wasstirred at 25° C. for 16 hours to give a mixture. The reaction wasquenched with sat.NH₄Cl (10 mL), and the mixture was extracted withCH₂Cl₂ (10 mL×2). The combined organic phase was washed with brine (10mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by Prep-HPLC (Waters Xbridge(150 mm×25 mm, 5 μm), A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 52-69% B over 6minutes) to give the product (60.97 mg, 0.13 mmol, 34% yield) as asolid. ¹H NMR DMSO-d₆+D₂O 400 MHz δ_(H)=7.79-7.74 (m, 2H), 7.58 (s, 1H),7.45-7.37 (m, 4H), 3.96-3.83 (m, 2H), 3.38-3.29 (m, 2H), 3.23-3.14 (m,1H), 3.06-3.00 (m, 1H), 2.84 (s, 3H), 2.80-2.70 (m, 1H), 2.07-1.94 (m,1H), 1.78-1.64 (m, 1H). LCMS R_(t)=1.35 min in 2.0 min chromatograph, MSESI calcd. for C₂₀H₂₀F₃N₂O₅S [M+H]⁺ 457.1, found 457.0.

Example 107. Synthesis of Compound 129

A mixture of3-[[(3R)-pyrrolidin-3-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-onehydrochloride (200 mg, 0.48 mmol), Et₃N (0.33 mL, 2.41 mmol) and methylcarbonochloridate (91.13 mg, 0.96 mmol) in DCM (25 mL) was stirred at20° C. for 16 hours. The reaction was diluted with sat.NH₄Cl (20 mL),and extracted with DCM (10 mL×2). The combined organic phase was washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by Prep-HPLC (WatersXbridge (150 mm×25 mm, 5 μm), A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 55-65%B over 7 minutes) to give the product (53.76 mg, 0.12 mmol, 25% yield)as a solid. ¹H NMR DMSO-d₆+D₂O 400 MHz δ_(H)=7.78 (d, 2H), 7.61 (s, 1H),7.50-7.33 (m, 4H), 3.88 (d, 2H), 3.57-3.46 (m, 3H), 3.45-3.34 (m, 2H),3.28-3.18 (m, 1H), 3.15-3.03 (m, 1H), 2.80-2.68 (m, 1H), 2.03-1.90 (m,1H), 1.78-1.61 (m, 1H). LCMS R_(t)=1.41 min in 2 min chromatography, MSESI calcd. for C₂₁H₂₀F₃N₂O₅ [M+H]⁺ 437.1, found 437.1.

Example 108. Synthesis of Compound 130

A mixture of3-[[(3R)-pyrrolidin-3-yl]methyl]-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-onehydrochloride (200 mg, 0.48 mmol), Et₃N (0.33 mL, 2.41 mmol) andmethanesulfonyl chloride (110.46 mg, 0.96 mmol) in DCM (25 mL) wasstirred at 20° C. for 16 hours. The reaction was diluted with sat.NH₄Cl(20 mL), and the mixture was extracted with DCM (10 mL×2). The combinedorganic phase was washed with brine (10 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H₂O (10 mMNH₄HCO₃) and B=CH₃CN; 51-71% B over 6 minutes) to give the product(68.23 mg, 0.15 mmol, 31% yield) as a solid. ¹H NMR DMSO-d₆+D₂O 400 MHzδ_(H)=7.79 (d, 2H), 7.66-7.60 (m, 1H), 7.47-7.39 (m, 4H), 3.94-3.86 (m,2H), 3.41-3.30 (m, 2H), 3.24-3.15 (m, 1H), 3.09-3.01 (m, 1H), 2.86 (s,3H), 2.80-2.70 (m, 1H), 2.07-1.93 (m, 1H), 1.79-1.66 (m, 1H). LCMSR_(t)=1.28 min in 2 min chromatography, MS ESI calcd. for C₂₀H₂₀F₃N₂O₅S[M+H]⁺ 457.1, found 456.8.

Example 109. Synthesis of Compound 131

To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one(100 mg, 0.34 mmol), pyrazin-2-ylmethanol (111.9 mg, 1.02 mmol) and PPh₃(177.7 mg, 0.68 mmol) in THF (6 mL) was added the DIAD (136.99 mg, 0.68mmol) at 0° C. and the mixture was stirred under N₂ at 20° C. for 16hours to give the mixture. The mixture was concentrated to dryness,diluted with H₂O (10 mL), and extracted with EtOAc (10 mL×2). Thecombined organic phase was washed with brine (10 mL), dried over Na₂SO₄,filtered and the filtrate was concentrated to give the crude product.The crude product was purified by flash chromatography on silica gel(EtOAc in PE=0% to 35% to 45% to 60%) to give the product (100.9 mg,260.4 μmol, 77% yield) as an oil. ¹H NMR DMSO-d₆ 400 MHz δ_(H)=8.83 (s,1H), 8.60-8.53 (m, 2H), 7.74 (d, 2H), 7.63 (s, 1H), 7.50-7.42 (m, 4H),5.35 (s, 2H). LCMS R_(t)=1.52 min in 2 min chromatography, MS ESI calcd.for C19HDF₃N303 [M+H]⁺ 388.1, found 388.1.

Example 110. Synthesis of Compound 132

To a mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one(100 mg, 0.34 mmol), pyrimidin-4-ylmethanol (111.9 mg, 1.02 mmol) andPPh₃ (177.7 mg, 0.68 mmol) in THF (6 mL) was added the DIAD (136.99 mg,0.68 mmol) at 0° C. and the mixture was stirred under N₂ at 20° C. for16 hours. The mixture was concentrated to dryness, diluted with H₂O (10mL), and the mixture was extracted with EtOAc (10 mL×2). The combinedorganic phase was washed with brine (10 mL), dried over Na₂SO₄, filteredand the filtrate was concentrated to give the crude product. The crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=0% to 30% to 40% to 55%) to give the product (62.94 mg, 160.4 47%yield) as colorless oil. ¹H NMR DMSO-d₆ 400 MHz δ_(H)=9.09 (s, 1H), 8.79(d, 1H), 7.74 (d, 2H), 7.63-7.59 (m, 2H), 7.51-7.41 (m, 4H), 5.30 (s,2H). LCMS R_(t)=1.27 min in 2 min chromatography, MS ESI calcd. forC₁₉H₁₃F₃N₃O₃ [M+H]⁺ 388.1, found 387.8.

Example 111. Synthesis of Compound 133

To a mixture of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (200 mg,0.68 mmol), tert-butyl 3-hydroxypropanoate (296.11 mg, 2.03 mmol) andPPh₃ (354.21 mg, 1.35 mmol) in THF (5 mL) was added the DIAD (273.07 mg,1.35 mmol) at 0° C. and the mixture was stirred under N₂ at 20° C. for16 hours. The mixture was concentrated to dryness, diluted with H₂O (10mL), and the mixture was extracted with EtOAc (10 mL×2). The combinedorganic phase was washed with brine (10 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 20% to30% to 45%) to give the product (255 mg, 0.49 mmol, 72% yield) as anoil. LCMS R_(t)=0.93 min in 1.5 min chromatography, MS ESI calcd. forC₂₀H₁₉F₃N₂O₅Na [M+Na]⁺ 447.1, found 447.1.

A mixture of tert-butyl3-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]propanoate(250 mg, 0.59 mmol) in TFA (3 mL) and DCM (6 mL) was stirred at 20° C.for 2 hour. From LCMS, desired MS was observed, and no starting materialwas remained. The mixture was concentrated to dryness to give the crudeproduct (210 mg, 0.33 mmol) as an oil, which was used directly withoutany further purification. LCMS R_(t)=0.94 min in 1.5 min chromatography,MS ESI calcd. for C₁₆H₁₂F₃N205 [M+H]⁺ 369.1, found 369.1.

To a mixture of3-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridinyl]propanoic acid (210.01 mg, 0.57 mmol), HATU (216.83 mg, 0.57 mmol),DIPEA (0.33 mL, 1.9 mmol) in DMF (6 mL) was added N-methylmethanaminehydrochloride (31 mg, 0.38 mmol), and the mixture was stirred at 20° C.for 4 hours. The mixture was diluted with H₂O (10 mL) and extracted withEtOAc (10 mL×3). The combined organic phase was washed with brine (10mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by flash chromatography onsilica gel (DCM) to give the product (25.31 mg, 62.4 μmol, 16% yield) asa solid. ¹H NMR DMSO-d₆ 400 MHz δ_(H)=8.18 (d, 2H), 7.84-7.73 (m, 2H),7.48 (d, 2H), 4.09 (t, 2H), 2.99-2.87 (m, 5H), 2.80 (s, 3H). LCMSR_(t)=1.27 min in 2 min chromatography, MS ESI calcd. for C₁₈H₁₇F₃N₃O₄[M+H]⁺ 396.1, found 396.1.

Example 112. Synthesis of Compound 134

To a solution of2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]aceticacid (195 mg, 0.55 mmol) in DMF (5 mL) was added HATU (313.96 mg, 0.83mmol), DIPEA (0.48 mL, 2.75 mmol) and (2R)-2-methylpyrrolidine (56.25mg, 0.66 mmol). The resulting mixture was stirred at 25° C. for 16 hoursto give a solution. Saturated NH₄Cl aqueous (20 mL) and EtOAc (20 mL)were added to the reaction mixture and stirred for 5 minutes. Afterseparated, the organic layer was washed with water (20 mL×2) and brine(20 mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-TLC(silica gel, PE:EtOAc=1:1) to give the product (145.29 mg, 0.34 mmol,63% yield) as a solid. ¹H NMR DMSO-d₆ 400 MHz δ_(H)=8.19-8.11 (m, 2H),7.91-7.85 (m, 1H), 7.84-7.77 (m, 1H), 7.49 (d, 2H), 4.74 (s, 2H),4.37-4.29 (m, 0.3H), 4.08-3.96 (m, 0.7H), 3.76-3.55 (m, 1.4H), 3.41-3.35(m, 0.6H), 2.10-1.79 (m, 3H), 1.76-1.50 (m, 1H), 1.31 (d, 1H), 1.10 (d,2H). LCMS R_(t)=1.20 min in 2.0 min chromatography, MS ESI calcd. forC₂₀H₁₉F₃N₃O₄ [M+H]⁺ 422.1, found 422.1.

Example 113. Synthesis of Compound 135

To a solution of2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridin-3-yl]aceticacid (195 mg, 0.55 mmol) in DMF (5 mL) was added HATU (313.96 mg, 0.83mmol), DIPEA (0.48 mL, 2.75 mmol) and (2S)-2-methylpyrrolidinehydrochloride (80.33 mg, 0.66 mmol). The resulting mixture was stirredat 25° C. for 16 hours to give a solution. Saturated NH₄Cl aqueous (20mL) and EtOAc (20 mL) were added to the reaction mixture and stirred for5 minutes. After separated, the organic layer was washed with water (20mL×2), brine (20 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby Prep-TLC (silica gel, PE:EtOAc=1:1) to give the product (77.38 mg,0.18 mmol, 33% yield) as a solid. ¹H NMR DMSO-d₆ 400 MHz δ_(H)=8.18-8.12(m, 2H), 7.91-7.86 (m, 1H), 7.83-7.78 (m, 1H), 7.49 (d, 2H), 4.95-4.65(m, 2H), 4.37-4.29 (m, 0.3H), 4.08-3.96 (m, 0.7H), 3.75-3.54 (m, 1.4H),3.40-3.35 (m, 0.6H), 2.11-1.79 (m, 3H), 1.76-1.50 (m, 1H), 1.31 (d, 1H),1.10 (d, 2H). LCMS R_(t)=1.20 min in 2.0 min chromatography, MS ESIcalcd. for C₂oH₁₉F₃N₃O₄ [M+H]⁺ 422.1, found 422.1.

Example 114. Synthesis of Compound 136

A mixture of5-bromo-3-(2-pyrimidin-2-ylethyl)oxazolo[4,5-b]pyridin-2-one (40 mg,0.12 mmol),2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(168.21 mg, 0.62 mmol), K₃PO₄ (52.89 mg, 0.25 mmol) and Pd(t-Bu₃P)₂(9.55 mg, 0.02 mmol) in 1,4-Dioxane (4 mL) and Water (0.40 mL) wasstirred at 80° C. under N₂ for 16 hours to give a suspension. Thereaction mixture was cooled to room temperature and filtered throughCelite. The filtrate was concentrated to give the crude product. Thecrude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) togive the product (14.82 mg, 38.6 μmol, 31% yield) as a solid. ¹H NMRCDCl₃, 400 MHz δ_(H)=8.62 (d, 2H), 7.93 (d, 2H), 7.43 (s, 2H), 7.20 (d,2H), 7.09 (t, 1H), 6.57 (t, 1H), 4.53 (t, 2H), 3.56 (t, 2H). LCMSR_(t)=1.22 min in 2.0 min chromatography, MS ESI calcd. for C₁₉H₁₅F2N403[M+H]⁺ 385.1, found 385.1.

Example 115. Synthesis of Compound 137

To a solution of 5-bromo-3H-oxazolo[4,5-b]pyridin-2-one (300 mg, 1.4mmol) in THF (5 mL) was added tert-butyl 2-hydroxyacetate (553.23 mg,4.19 mmol), PPh₃ (731.97 mg, 2.79 mmol) and then DIAD (564.31 mg, 2.79mmol). The resulting mixture was stirred at 25° C. under N₂ for 16 hoursto give a solution. The reaction solution was concentrated to give aresidue. Water (20 mL) was added to the residue, and the mixture wasextracted with EtOAc (20 mL×2). The combined organic layer was washedwith brine (20 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=0% to 10% to 30%) togive the product (400 mg, 1.22 mmol, 87% yield) as a solid. ¹H NMRCDCl₃, 400 MHz δ_(H)=7.33-7.29 (m, 1H), 7.27-7.24 (m, 1H), 4.55 (s, 2H),1.48 (s, 9H).

A mixture of tert-butyl2-(5-bromo-2-oxo-oxazolo[4,5-b]pyridin-3-yl)acetate (100 mg, 0.30 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(117.06 mg, 0.36 mmol), K₃PO₄ (129 mg, 0.61 mmol) and Pd(t-Bu₃P)₂ (23.29mg, 0.05 mmol) in 1,4-Dioxane (10 mL) and Water (1 mL) was stirred at80° C. under N₂ for 16 hours to give a suspension. The reaction mixturewas cooled to room temperature and filtered through Celite. The filtratewas concentrated to give the crude product. The crude product waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to20%) to give the product (120 mg, 0.27 mmol, 89% yield) as a solid. ¹HNMR (CDCl₃, 400 MHz) δ_(H)=8.47 (s, 1H), 8.03 (d, 1H), 7.55-7.40 (m,2H), 4.90 (q, 2H), 4.62 (s, 2H), 1.50 (s, 9H).

To a solution of tert-butyl2-[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-2-oxo-oxazolo[4,5-b]pyridin-3-yl]acetate(120 mg, 0.27 mmol) in DCM (5 mL) was added TFA (2.78 mL). The resultingmixture was stirred at 25° C. for 2 hours to give a solution. Thereaction solution was concentrated to give the crude product (100 mg,0.25 mmol, 95.40% yield) as a solid. ¹H NMR DMSO-d₆ 400 MHz 6=8.75 (d,1H), 8.47 (d, 1H), 7.96-7.85 (m, 2H), 5.15 (q, 2H), 4.71 (s, 2H).

To a solution of2-[5-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-2-oxo-oxazolo[4,5-b]pyridin-3-yl]aceticacid (100 mg, 0.26 mmol) in DMF (5 mL) was added HATU (147.28 mg, 0.39mmol), DIPEA (0.14 mL, 0.77 mmol) and pyrrolidine (27.55 mg, 0.39 mmol).The resulting mixture was stirred at 25° C. for 16 hours to give asolution. Saturated NH₄Cl aqueous (20 mL) was added to the reactionmixture, and the mixture was extracted with EtOAc (20 mL×2). Thecombined organic phase was washed with brine (20 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated to give the crude product.The crude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) togive the product (34.11 mg, 75.5 μmol, 29% yield) as a solid. ¹H NMR(CDCl₃, 400 MHz) δ_(H)=8.44 (d, 1H), 8.03 (dd, 1H), 7.50 (d, 1H), 7.43(d, 1H), 4.89 (q, 2H), 4.69 (s, 2H), 3.62 (t, 2H), 3.54 (t, 2H), 2.11(quin, 2H), 1.94 (quin, 2H). LCMS R_(t)=1.27 min in 2.0 minchromatography, MS ESI calcd. for C₁₉H₁₇F₄N₄O₄ [M+H]⁺ 441.1, found441.0.

Example 116. Synthesis of Compound 138 and Compound 139

To the mixture of2-[2-oxo-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-3-yl]acetic acid(500 mg, 1.42 mmol), DIPEA (0.74 mL, 4.25 mmol) and HATU (1.61 g, 4.25mmol) in DMF (10 mL) was added the 3-(methoxymethyl)pyrrolidinehydrochloride (321.93 mg, 2.12 mmol), and the mixture was stirred at 25°C. for 2 hours to give the solution. The mixture was diluted with H₂O(10 mL) and extracted with EtOAc (20 mL×2). The combined organic phasewas washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=20% to 50% to 100%)to give the impure product. The impure product was further purified byPrep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm), A=H₂O (0.05% NH₄OH) andB=CH₃CN; 50-80% B over 8 minutes) to give the product (150 mg).

The product was separated by SFC (04250 mm×30 mm,5 μm); A=CO₂ and B=EtOH(0.1% NH₃H₂O); 20° C.; 50 mL/min; 30% B; 7 min run; 14 injections, Rt ofpeak 1 =4.90 min, Rt of Peak 2=5.82 min) to give the compound 138 (35.08mg, 77.9 μmol) (Peakl, R_(t)=2.90 min in SFC) as a solid and compound139 (42.87 mg, 95.2 μmol) (Peak2, R_(t)=3.21 min in SFC) as a solid.Note: the enantiomers were randomly assigned.

Compound 138: ¹H NMR DMSO-d₆+D₂O 400 MHz δ_(H)=7.71 (d, 2H), 7.45-7.36(m, 5H), 4.76-4.59 (m, 2H), 3.72-3.59 (m, 1H), 3.57-3.16 (m, 8H),3.04-2.98 (m, 0.5H), 2.41-2.36 (m, 0.5H), 2.07-1.86 (m, 1H), 1.73-1.50(m, 1H). LCMS R_(t)=1.28 min in 2.0 min chromatography, MS ESI calcd.for C₂₂H₂₂F₃N₂O₅ [M+H]⁺ 451.1, found 451.0.

Compound 139: ¹H NMR DMSO-d₆+D₂O 400 MHz δ_(H)=7.72 (d, 2H), 7.50-7.36(m, 5H), 4.79-4.61 (m, 2H), 3.75-3.59 (m, 1H), 3.55-3.12 (m, 8H),3.06-2.97 (m, 0.5H), 2.41-2.36 (m, 0.5H), 2.09-1.86 (m, 1H), 1.75-1.47(m, 1H). LCMS R_(t)=1.27 min in 2.0 min chromatography, MS ESI calcd.for C₂₂H₂₂F₃N₂O₅ [M+H]⁺ 451.1, found 451.1.

Example 117. Synthesis of Compound 140

A mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (100mg, 0.34 mmol), chloro(methylsulfanyl)methane (65.43 mg, 0.68 mmol) andCs₂CO₃ (220.72 mg, 0.68 mmol) in DMF (2 mL) was stirred at 55° C. for 16hours to give a mixture. After cooling to r.t., the mixture was dilutedwith H₂O (20 mL), and the mixture was extracted with EtOAc (20 mL×2).The combined organic phase was washed with brine (15 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography on silica gel (EtOAc in PE=0% to 10% to 30%) to give theproduct 110 mg, 0.31 mmol, 91% yield) as a solid. ¹H NMR DMSO-d₆ 400 MHzδ_(H)=7.83-7.75 (m, 3H), 7.52-7.44 (m, 4H), 5.11 (s, 2H), 2.17 (s, 3H).

To a solution of3-(methylsulfanylmethyl)-5-[4-(trifluoromethoxy)phenyl]-1,3-benzoxazol-2-one(110 mg, 0.31 mmol) in DCM (10 mL) was added m-CPBA (160.27 mg, 0.93mmol). The reaction mixture was stirred at 20° C. for 2 hours to give asolution. The reaction mixture was quenched with sat.NaHCO₃ (20 mL),extracted with DCM (10 mL×3). The combined organic phase was washed withbrine (10 mL), dried over Na₂SO₄, filtered and concentrated. The residuewas purified by flash chromatography on silica gel (EtOAc in PE =0% to15% to 30%) to give the product (69.04 mg, 0.18 mmol, 57% yield) as asolid. ¹H NMR DMSO-d₆ 400 MHz δ_(H)=7.83-7.75 (m, 3H), 7.54-7.47 (m,4H), 5.49 (s, 2H), 3.15 (s, 3H). LCMS R_(t)=1.27 min in 2.0 minchromatography. MS MS ESI calcd. for C₁₆H₁₂F₃NO₅SNa [M+Na]⁺ 410.0286,found 410.0282.

Example 118. Synthesis of Compound 141

A mixture of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg,0.34 mmol), pyrimidin-4-ylmethanol (74.35 mg, 0.68 mmol), PPh₃ (177.1mg, 0.68 mmol) and DIAD (136.54 mg, 0.68 mmol) in THF (3 mL) was stirredat 20° C. under N₂ for 16 hours. The reaction was quenched withsat.NH₄Cl (10 mL), and the mixture was extracted with EtOAc (10 mL×2).The combined organic phase was washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated to give the crude product. The crudeproduct was purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm),A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 45-75% B over 7 minutes) to give theproduct (68.81 mg, 0.18 mmol, 52% yield) as a solid. ¹H NMR DMSO-d₆ 400MHz δ_(H)=9.10 (d, 1H), 8.81 (d, 1H), 8.07 (d, 2H), 7.90 (d, 1H), 7.81(d, 1H), 7.74-7.70 (m, 1H), 7.44 (d, 2H), 5.27 (s, 2H). LCMS R_(t)=1.27min in 2.0 min chromatography, MS ESI calcd. for C₁₈H₁₂F₃N₄O₃ [M+H]⁺389.1, found 389.0.

Example 119. Synthesis of Compound 142

To the mixture of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (200 mg,0.68 mmol), 1-(2-hydroxyethyl)pyrrolidin-2-one (261.63 mg, 2.03 mmol)and PPh₃ (354.21 mg, 1.35 mmol) in THF (6 mL) was added DIAD (273.07 mg,1.35 mmol) at 0° C. and the mixture was stirred under N₂ at 20° C. for16 hours to give the mixture. The mixture was concentrated to dryness,diluted with H₂O (10 mL), and the mixture was extracted with EtOAc (20mL×2). The combined organic phase was washed with brine (10 mL), driedover Na₂SO₄, filtered and the filtrate was concentrated to give thecrude product. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 30% to 40% to 55%) to give the product(127.94 mg, 0.31 mmol, 47% yield) as a solid. ¹H NMR DMSO-d₆ 400 MHzδ_(H)=8.21 (d, 2H), 7.84-7.73 (m, 2H), 7.50 (d, 2H), 4.11-4.02 (m, 2H),3.60 (t, 2H), 3.51 (t, 2H), 1.89-1.79 (m, 2H), 1.75-1.60 (m, 2H). LCMSR_(t)=1.14 min in 2 min chromatography, MS ESI calcd. for C₁₉H₁₇F₃N₃O₄[M+H]⁺ 408.1, found 408.0.

Example 120. Synthesis of Compound 143

A mixture of pyrazin-2-ylmethanol (74.35 mg, 0.68 mmol),5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg,0.34 mmol), PPh₃ (177.10 mg, 0.68 mmol) and DIAD (136.54 mg, 0.68 mmol)in THF (3 mL) was stirred at 20° C. for 16 hours. The reaction wasdiluted with sat.NH₄Cl (20 mL), and the mixture was extracted with DCM(20 mL×2). The combined organic phase was washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated to give the crude product.The crude product was purified by Prep-HPLC (Waters Xbridge (150 mm×25mm, 5 μm), A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 42-72% B over 7 minutes)to give the product (64.4 mg, 0.17 mmol, 49% yield) as a solid. ¹H NMR(DMSO-d₆ 400 MHz) δ_(H)=8.91 (s, 1H), 8.64-8.54 (m, 2H), 8.08 (d, 2H),7.89-7.78 (m, 2H), 7.44 (d, 2H), 5.32 (s, 2H). LCMS R_(t)=1.17 min in 2min chromatography, MS ESI calcd. for C₁₈H₁₂F₃N₄O₃ [M+H]⁺ 389.1, found389.0.

Example 121. Synthesis of Compound 144

A mixture of tert-butyl2-(5-bromo-2-oxo-oxazolo[4,5-b]pyridin-3-yl)acetate (100 mg, 0.30 mmol),4,4,5,5-tetramethyl-2-[2-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane(110.14 mg, 0.36 mmol), K₃PO₄ (129 mg, 0.61 mmol) and Pd(t-Bu₃P)₂ (23.29mg, 0.05 mmol) in 1,4-Dioxane (5 mL) and water (0.50 mL) was stirred at80° C. under N₂ for 16 hours to give a suspension. The reaction mixturewas cooled to room temperature and filtered through Celite. The filtratewas concentrated to give the residue (120 mg). Water (15 mL) was addedto the residue, and the resulting mixture was extracted with EtOAc (20mL×2). The combined organic phase was washed with brine (15 mL×2), driedover anhydrous Na₂SO₄, filtered and concentrated to give the crudeproduct (110 mg). The crude product was purified by flash chromatographyon silica gel (EtOAc in PE=0% to 10% to 20%) to give the product (100mg, 0.21 mmol, 71% yield) as colorless oil. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=7.51 (d, 1H), 7.38 (d, 1H), 7.18-7.09 (m, 3H), 4.59 (s, 2H), 2.37(s, 3H), 1.48 (s, 9H).

To a solution of tert-butyl2-[5-[2-methyl-4-(trifluoromethoxy)phenyl]-2-oxo-oxazolo[4,5-b]pyridin-3-yl]acetate(100 mg, 0.24 mmol) in DCM (5 mL) was added TFA (2.5 mL). The resultingsolution was stirred at 25° C. for 1 hour to give a solution. Thereaction solution was concentrated to give the crude product (86 mg,0.23 mmol, 99% yield) as a grey solid which was used to next stepdirectly without further purification. LCMS R_(t)=0.94 min in 1.5 minchromatography, MS ESI calcd. for C₁₆H₁₂F₃N₂O₅ [M+H]⁺ 369.1, found369.0.

To a solution of2-[5-[2-methyl-4-(trifluoromethoxy)phenyl]-2-oxo-oxazolo[4,5-b]pyridin-3-yl]aceticacid (86 mg, 0.23 mmol) in DMF (5 mL) was added HATU (133.19 mg, 0.35mmol), DIPEA (0.12 mL, 0.70 mmol) and pyrrolidine (19.93 mg, 0.28 mmol).The resulting mixture was stirred at 25° C. for 16 hours to give asolution. Water (20 mL) was added to the reaction solution, and themixture was extracted with EtOAc (30 mL×2). The combined organic phasewas washed with water (20 mL×2) and brine (20 mL×2), dried overanhydrous Na₂SO₄, filtered and concentrated to give the crude product.The crude product was purified by Prep-TLC (silica gel, PE:EtOAc=1:1) togive the product (41.09 mg, 95.4 μmol, 41% yield) as a solid. ¹H NMR(CDCl₃, 400 MHz) δ_(H)=7.50 (d, 1H), 7.39 (d, 1H), 7.15-7.09 (m, 3H),4.66 (s, 2H), 3.67-3.45 (m, 4H), 2.35 (s, 3H), 2.04 (quin, 2H), 1.89(quin, 2H). LCMS R_(t)=1.35 min in 2.0 min chromatography, MS ESI calcd.for C₂₀H₁₉F₃N304 [M+H]⁺ 422.1, found 422.0.

Example 122. Synthesis of Compound 145

A mixture of tert-butyl 2-5-bromo-2-oxo-oxazolo[4,5]pyridin-3-yl)acetate (100 mg, 0.30 mmol),2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3 ,2-dioxaborolane(98.46 mg, 0.36 mmol), K₃PO₄ (129 mg, 0.61 mmol) and Pd(t-Bu₃P)₂ (23.29mg, 0.05 mmol) in 1,4-dioxane (5 mL) and water (0.50 mL) was stirred at80° C. under N₂ for 16 hours. The reaction mixture was cooled to roomtemperature and filtered through Celite. The filtrate was concentratedto give the residue (90 mg). Water (15 mL) was added to the residue, andthe resulting mixture was extracted with EtOAc (20 mL×2). The combinedorganic phase was washed with brine (15 mL×2), dried over anhydrousNa₂SO₄, filtered and concentrated. The crude product was purified byflash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) togive the product (90 mg, 0.22 mmol, 73% yield) as a solid. ¹H NMR(CDCl₃, 400 MHz) δ_(H)=7.95 (d, 2H), 7.48 (s, 2H), 7.21 (d, 2H),6.81-6.34 (m, 1H), 4.63 (s, 2H), 1.49 (s, 9H).

To a solution of tert-butyl2-[5-[4-(difluoromethoxy)phenyl]-2-oxo-oxazolo[4,5-b]pyridin-3-yl]acetate(90 mg, 0.23 mmol) in DCM (5 mL) was added TFA (2.5 mL). The resultingsolution was stirred at 25° C. for 2 hours. The reaction solution wasconcentrated to give the crude product (75 mg, 0.22 mmol, 99% yield) asa grey solid, which was used to the next step directly without furtherpurification. LCMS R_(t)=0.76 min in 1.5 min chromatography, MS ESIcalcd. for C₁₅H₁₁F₂N₂O₅ [M+H]⁺ 337.1, found 336.9.

To a solution of2-[5-[4-(difluoromethoxy)phenyl]-2-oxo-oxazolo[4,5-b]pyridin yl]aceticacid (75 mg, 0.22 mmol) in DMF (3 mL) was added HATU (127.21 mg, 0.33mmol), DIPEA (0.12 mL, 0.67 mmol) and pyrrolidine (31.73 mg, 0.45 mmol).The resulting mixture was stirred at 25° C. for 16 hours. Water (15 mL)was added to the reaction solution, and the mixture was extracted withEtOAc (20 mL×2). The combined organic layer was washed with brine (20mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=10% to 30% to 50%) to give theproduct (24.63 mg, 0.06 mmol, 27% yield) as a solid. ¹H NMR (CDCl₃, 400MHz) δ_(H)=7.92 (d, 2H), 7.50-7.42 (m, 2H), 7.20 (d, 2H), 6.56 (t, 1H),4.70 (s, 2H), 3.61 (t, 2H), 3.54 (t, 2H), 2.09 (quin, 2H), 1.92 (quin,2H). LCMS R_(t)=1.17 min in 2.0 min chromatography, MS ESI calcd. forC₁₉H₁₈F₂N₃O₄ [M+H]⁺ 390.1, found 390.0.

Example 123. Synthesis of Compound 146

A mixture of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg,0.34 mmol), 2-pyrimidin-4-ylethanol (83.82 mg, 0.68 mmol), PPh₃ (177.10mg, 0.68 mmol) and DIAD (136.54 mg, 0.68 mmol) in THF (3 mL) was stirredat 20° C. under N₂ for 16 hours. The reaction was diluted with sat.NH₄Cl(10 mL), and the mixture was extracted with EtOAc (10 mL×2). Thecombined organic phase was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=40% to70%) to give the product (53.90 mg, 0.13 mmol, 39% yield) as solid. ¹HNMR (DMSO-d₆+D₂O 400 MHz) δ_(H)=8.94 (s, 1H), 8.59 (d, 1H), 8.03 (d,2H), 7.76-7.63 (m, 2H), 7.52-7.40 (m, 3H), 4.28 (t, 2H), 3.26 (t, 2H).LCMS R_(t)=1.28 min in 2 min chromatography, MS ESI calcd. forC₁₉H₁₄F₃N₄O₃ [M+H]⁺ 403.1, found 403.1.

Example 124. Synthesis of Compound 147

A mixture of 5-[4-(trifluoromethoxy)phenyl]-3H-1,3-benzoxazol-2-one (100mg, 0.34 mmol), 2-pyrimidin-4-ylethanol (83.82 mg, 0.68 mmol), PPh₃(177.1 mg, 0.68 mmol) and DIAD (136.54 mg, 0.68 mmol) in THF (3 mL) wasstirred at 20° C. under N₂ for 16 hours.

The reaction was quenched with sat.NH₄Cl (10 mL), and the mixture wasextracted with EtOAc (10 mL×2). The combined organic phase was washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=40% to 80%) to give the impureproduct. The impure product was purified by Prep-HPLC (Waters Xbridge(150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 43-73% B over 6minutes) to give the product (17.19 mg, 42.8 μmol, 13% yield) as asolid,. ¹H NMR (DMSO-d6400 MHz) δ_(H)=9.06 (d, 1H), 8.68 (d, 1H), 7.78(d, 2H), 7.59 (s, 1H), 7.52 (dd, 1H), 7.47 (d, 2H), 7.42 (d, 2H), 4.30(t, 2H), 3.23 (t, 2H). LCMS R_(t)=1.18 min in 2.0 min chromatography, MSESI calcd. for C₂₀H15F₃N303 [M+H]⁺ 402.1, found 402.1.

Example 125. Synthesis of Compound 148

To a mixture of 5-bromo-3H-1,3-benzoxazol-2-one (500 mg, 2.34 mmol) andCs₂CO₃ (1.52 g, 4.67 mmol) in DMF (10 mL) was added tert-butyl2-bromoacetate (911.36 mg, 4.67 mmol). The reaction mixture was stirredat 55° C. for 16 hours to give a mixture. After cooling to r.t., themixture was diluted with H₂O (20 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was triturated from PE (5 mL) to give theproduct (660 mg, 2.01 mmol, 86% yield) as a solid. ¹H NMR (DMSO-d₆ 400MHz) δ_(H)=7.66 (d, 1H), 7.41-7.27 (m, 2H), 4.65 (s, 2H), 1.42 (s, 9H).

To a mixture of tert-butyl 2-(5-bromo-2-oxo-1,3-benzoxazol-3-yl)acetate(200 mg, 0.61 mmol),2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(197.52 mg, 0.73 mmol), K₃PO₄ (258.78 mg, 1.22 mmol) and Pd(t-Bu₃P)₂(62.29 mg, 0.12 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL) wasstirred at 80° C. for 16 hours under N₂. After cooling to r.t., themixture was diluted with H₂O (10 mL) and extracted with EtOAc (20 mL×2).The combined organic phase was washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated to give the crude product. The crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=0% to 4% to 8% to 15%) to give the product (180 mg, 0.46 mmol, 75%yield) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=7.83-7.61 (m, 3H),7.55-7.04 (m, 5H), 4.72 (s, 2H), 1.43 (s, 9H).

A mixture of tert-butyl2-[5-[4-(difluoromethoxy)phenyl]-2-oxo-1,3-benzoxazol-3-yl]acetate (180mg, 0.46 mmol) in TFA (3 mL) and DCM (6 mL) was stirred at 15° C. for 4hours. The mixture was concentrated to dryness to give the product (150mg, 0.45 mmol, 97% yield) as a solid. ¹H NMR (DMSO-d₆ 400 MHz)δ_(H)=7.80-7.66 (m, 3H), 7.55-7.04 (m, 5H), 4.71 (s, 2H).

A mixture of2-[5-[4-(difluoromethoxy)phenyl]-2-oxo-1,3-benzoxazol-3-yl]acetic acid(130 mg, 0.39 mmol), HATU (294.88 mg, 0.78 mmol), and DIPEA (0.27 mL,1.55 mmol) in DMF (6 mL) was stirred at 25° C. for 10 min. Then to themixture was added pyrrolidine (41.37 mg, 0.58 mmol), and the mixture wasstirred at 25° C. for 8 hours. The mixture was diluted with H₂O (10 mL)and extracted with DCM (10 mL×2). The combined organic phase was washedwith brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by prep-HPLC (Kromasil(150 mm×25 mm, 5 μm), A=H₂O (0.05% NH₄OH) and B=CH₃CN; 40-70% B over 7minutes) to give the product (23.5 mg, 60.5 μmol, 16% yield) as a solid.¹H NMR (DMSO-dδ400 MHz) δ_(H)=7.69 (d, 2H), 7.53 (s, 1H), 7.47-6.97 (m,5H), 4.73 (s, 2H), 3.56 (t, 2H), 3.30 (t, 2H), 2.00-1.87 (m, 2H),1.86-1.70 (m, 2H). LCMS R_(t)=1.11 min in 2 min chromatography, MS ESIcalcd. for C₂₀oH₁₉F₂N₂O₄ [M+H]⁺ 389.1, found 389.1.

Example 126. Synthesis of Compound 149 and Compound 150

To a mixture of ethyl 2-pyrimidin-2-ylacetate (900 mg, 5.42 mmol) in THF(20 mL) was added LDA (3.25 mL, 6.5 mmol) at −78° C., then the mixturewas stirred at −78° C. for 2 hours. To the mixture was added iodomethane(922.46 mg, 6.5 mmol), then the mixture was stirred at −78° C. to 20° C.for 3 hours. The mixture was quenched with sat. NH₄Cl (30 mL), then themixture was extracted with EtOAc (50 mL×2). The combined organic phasewas washed with water (20 mL) and brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=0% to20% to 45%) to give the product (730 mg, 4.05 mmol, 75% yield) as oil.¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.72 (d, 2H), 7.19 (t, 1H), 4.19 (q, 2H),4.14-4.07 (m, 1H), 1.62 (d, 3H), 1.22 (t, 3H).

To a mixture of ethyl 2-pyrimidin-2-ylpropanoate (650 mg, 3.61 mmol) inTHF (20 mL) was added DIBAL-H (10.82 mL, 10.82 mmol) at 0° C., then themixture was stirred at 0° C. for 5 hours. The mixture was quenched withNa₂SO_(4.10) H₂O (20 g). The mixture was filtered through Celite, elutedwith THF (30 mL×2), the filtrate was concentrated to give the crudeproduct. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 50% to 100%) to give the product (150 mg,1.06 mmol, 29% yield) as an oil. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.70 (d,2H), 7.20 (t, 1H), 4.03-3.96 (m, 1H), 3.95-3.86 (m, 1H), 3.33-3.21 (m,1H), 1.39 (d, 3H). LCMS R_(t)=0.12 min in 1.5 min chromatography, MS ESIcalcd. for C₇H₁₁N₂O [M+H]⁺ 139.1, found 138.9.

To a solution of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg,0.34 mmol) in THF (5 mL) was added PPh₃ (177.1 mg, 0.68 mmol),2-pyrimidin-2-ylpropan-1-ol (139.94 mg, 1.01 mmol) and DIAD (136.54 mg,0.68 mmol). The resulting mixture was stirred at 25° C. under N₂ for 16hours to give a solution. The reaction solution was concentrated to givea residue. To the residue was added water (20 mL), and the mixture wasextracted with EtOAc (20 mL×2). The combined organic phase was washedwith water (15 mL×2) and brine (15 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=0% to10% to 20%) to give the product (130 mg) as a solid. LCMS R_(t)=1.38 minin 2.0 min chromatography, MS ESI calcd. for C₂₀H₁₆F₃N₄O₃ [M+H]⁺ 417.1,found 417.1.

The product was separated by SFC (Column: DAICEL CHIRALCEL OJ-H (250mm×30 mm, 5 μm); A=CO₂ and B=Neu-ETOH; 40° C.; 60 mL/min; 15% B; 11 minrun; 17 injections, Rt of peak 1=8.43 min, Rt of Peak 2=9.53 min) togive the Compound 149 (37.47 mg, 0.09 mmol, 27% yield, Peak 1) as asolid and Compound 150 (52.19 mg, 0.13 mmol, 37% yield, Peak 2) as asolid.

Compound 149 ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.61 (d, 2H), 7.94 (d, 2H),7.42 (s, 2H), 7.30 (d, 2H), 7.04 (t, 1H), 4.45-4.28 (m, 2H), 3.90-3.78(m, 1H), 1.52 (d, 3H). LCMS R_(t)=1.25 min in 2.0 min chromatography, MSESI calcd. for C₂₀H₁₆F₃N₄O₃ [M+H]⁺ 417.1, found 417.0.

Compound 150 ¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.61 (d, 2H), 7.94 (d, 2H),7.42 (s, 2H), 7.30 (d, 2H), 7.04 (t, 1H), 4.46-4.26 (m, 2H), 3.91-3.77(m, 1H), 1.52 (d, 3H). LCMS R_(t)=1.25 min in 2.0 min chromatography, MSESI calcd. for C₂₀H₁₆F₃N₄O₃ [M+H]⁺ 417.1, found 417.1.

Example 127. Synthesis of Compound 151

To a solution of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg,0.20 mmol), (1-methylpyrazol-4-yl)methanol (68.14 mg, 0.61 mmol) andPPh₃ (106.26 mg, 0.41 mmol) in THF (3 mL) was added DIAD (81.92 mg, 0.41mmol). The resulting mixture was stirred at 20° C. under N₂ for 16 hoursto give a solution. The reaction solution was concentrated to give aresidue. The residue was diluted with water (5 mL), extracted with EtOAc(10 mL×2). The combined organic layer was washed with water (5 mL×2),brine (5 mL×2), dried over anhydrous Na₂SO₄, filtered and concentratedto give the crude product.

The crude product was purified by flash chromatography on silica gel(EtOAc in PE =0% to 20% to 30%) to give the product (31.82 mg, 81.5μmol, 40% yield) as a solid. ¹H NMR (400 Mz, CDCl₃) δ_(H)=8.03 (d, 2H),7.67 (s, 1H), 7.57 (s, 1H), 7.50-7.42 (m, 2H), 7.35 (d, 2H), 5.03 (s,2H), 3.87 (s, 3H). LCMS R_(t)=1.26 min in 2.0 min chromatography, MS ESIcalcd. for C₁₈H₁₄F₃N₄O₃ [M+H]⁺ 391.1, found 390.9.

Example 128. Synthesis of Compound 152

To a solution of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg,0.20 mmol), (3,5-dimethylisoxazol-4-yl)methanol (77.26 mg, 0.61 mmol)and PPh₃ (106.26 mg, 0.41 mmol) in THF (3 mL) was added DIAD (81.92 mg,0.41 mmol). The resulting mixture was stirred at 20° C. under N₂ for 16hours to give a solution. The reaction solution was concentrated to givea residue. The residue was diluted with water (5 mL), extracted withEtOAc (10 mL×2). The combined organic layer was washed with water (5mL×2), brine (5 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=0% to 20% to 30%) togive the product (51.04 mg, 125.9 μmol, 62% yield) as a solid. NMR (400MHz, CDCl₃) δ_(H)=7.95 (d, 2H), 7.49 (s, 2H), 7.34 (d, 2H), 4.90 (s,2H), 2.61 (s, 3H), 2.43 (s, 3H). LCMS R_(t)=1.35 min in 2.0 minchromatography, MS ESI calcd. for C₁₉H₁₅F₃N304 [M+H]⁺ 406.1, found405.9.

Example 129. Synthesis of Compound 153

To a mixture of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg,0.20 mmol), PPh₃ (106.26 mg, 0.41 mmol) and(5-methyl-1,3,4-oxadiazol-2-yl)methanol (46.23 mg, 0.41 mmol) in THF (1mL) was added DIAD (81.92 mg, 0.41 mmol). The mixture was stirred at 20°C. under N₂ for 16 hours. The reaction was diluted with sat.NH₄Cl (10mL), and the mixture was extracted with EtOAc (15 mL×2). Then thecombined organic phase was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by Prep-HPLC(Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10mM NH₄HCO₃) and B=CH₃CN; 47-67% B over 6 minutes) to give the product(23.49 mg, 58.60 μmol, 29% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz)δ_(H)=7.96 (d, 2H), 7.54 (s, 2H), 7.32-7.28 (m, 2H), 5.37 (s, 2H), 2.54(s, 3H). LCMS R_(t)=1.12 min in 2 min chromatography, MS ESI calcd. forC₁₇H₁₂F₃N₄O₄ [M+H]⁺ 393.1, found 393.0.

Example 130. Synthesis of Compound 154

To a mixture of (5-methylisoxazol-4-yl)methanol (45.82 mg, 0.41 mmol),5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg,0.20 mmol) and PPh₃ (106.26 mg, 0.41 mmol) in THF (1 mL) was added DIAD(81.92 mg, 0.41 mmol). The mixture was stirred at 20° C. under N₂ for 16hours. The reaction was diluted with sat.NH₄Cl (10 mL), and the mixturewas extracted with EtOAc (10 mL×2). Then the combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=0% to 30%) to give the product(48.92 mg, 0.12 mmol, 62% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz,)δ_(H)=8.43 (s, 1H), 7.99 (d, 2H), 7.49 (d, 2H), 7.35 (d, 2H), 4.96 (s,2H), 2.63 (s, 3H). LCMS R_(t)=1.25 min in 2.0 min chromatography, MS ESIcalcd. for C₁₈H₁₃F₃N₃O₄ [M+H]⁺ 392.1, found 392.1.

Example 131. Synthesis of Compound 155

To a mixture of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg,0.20 mmol), PPh₃ (106.26 mg, 0.41 mmol) and(5-methyl-1,3,4-thiadiazol-2-yl)methanol (52.74 mg, 0.41 mmol) in THF (1mL) was added DIAD (81.92 mg, 0.41 mmol). The mixture was stirred at 20°C. under N₂ for 16 hours. The reaction was diluted with sat.NH₄Cl (10mL), and the mixture was extracted with EtOAc (15 mL×2). Then thecombined organic phase was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10mM NH₄HCO₃) and B=CH₃CN; 49-69% B over 6 minutes) to give the product(36.17 mg, 87.40 mmol, 43% yield) as a solid. ¹H NMR (DMSO-d₆ 400 MHz)δ_(H)=8.17 (d, 2H), 7.92-7.80 (m, 2H), 7.49 (d, 2H), 5.52 (s, 2H), 2.69(s, 3H). LCMS R_(t)=1.15 min in 2 min chromatography, MS ESI calcd. forC₁₇H₁₂F₃N₄O₃S [M+H]⁺ 409.1, found 409.0.

Example 132. Synthesis of Compound 156

To a mixture of (5-methylisoxazol-3-yl)methanol (45.82 mg, 0.41 mmol),5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg,0.20 mmol) and PPh₃ (106.26 mg, 0.41 mmol) in THF (3 mL) was added DIAD(81.92 mg, 0.41 mmol). The mixture was stirred at 20° C. under N₂ for 16hours. The reaction was diluted with sat.NH₄Cl (10 mL), and the mixturewas extracted with EtOAc (10 mL×2). Then the combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=0% to 30%) to give the product(52.56 mg, 0.13 mmol, 66% yield) as a solid. ¹H NMR (CDCl₃, 400 MHz,)δ_(H)=8.01 (d, 2H), 7.46-7.54 (m, 2H), 7.31 (d, 2H), 6.12 (s, 1H), 5.22(s, 2H), 2.40 (s, 3H). LCMS R_(t)=1.22 min in 2.0 min chromatography, MSESI calcd. for C₁₈H₁₃F₃N304 [M+H]⁺ 392.1, found 392.0.

Example 133. Synthesis of Compound 157

To a mixture of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg,0.2 mmol), (1-methyl-1,2,4-triazol-3-yl)methanol (45.83 mg, 0.41 mmol)and PPh₃ (106.26 mg, 0.41 mmol) in THF (1 mL) was added the DIAD (81.92mg, 0.41 mmol) , and the mixture was stirred at 20° C. under N₂ for 16hours. The reaction was diluted with sat.NH₄Cl (10 mL), and the mixturewas extracted with EtOAc (10 mL×2). Then the combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified by purified byprep-HPLC [Kromasil (150 mm×25 mm, 5 μm) A=H₂O (0.05% NH₄OH) andB=CH₃CN; 47-87% B over 7 minutes] to give the product (21.81 mg, 0.06mmol, 28% yield) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.40 (s,1H), 8.12 (d, 2H), 7.87 (d, 1H), 7.80 (d, 1H), 7.47 (d, 2H), 5.13 (s,2H), 3.80 (s, 3H). LCMS R_(t)=1.12 min in 2 min chromatography, MS ESIcalcd. for C₁₇H₁₃F₃N₅O₃ [M+H]⁺ 392.1, found 392.0.

Example 134. Synthesis of Compound 158

To a mixture of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg,0.2 mmol), (2-methylpyrazol-3-yl)methanol (45.43 mg, 0.41 mmol) and PPh₃(106.26 mg, 0.41 mmol) in THF (1 mL) was added the DIAD (81.92 mg, 0.41mmol), and the mixture was stirred at 20° C. under N₂ for 16 hours. Thereaction was diluted with sat.NH₄Cl (10 mL), and the mixture wasextracted with EtOAc (10 mL×2). Then the combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=20% to 70%) to give theproduct (9.03 mg, 23.1 mol, 11% yield) as a solid. ¹H NMR (DMSO-d₆ 400MHz) δ_(H)=8.18 (d, 2H), 7.88-7.77 (m, 2H), 7.50 (d, 2H), 7.35 (d, 1H),6.38 (d, 1H), 5.18 (s, 2H), 3.97 (s, 3H). LCMS R_(t)=1.20 min in 2.0 minchromatography, MS ESI calcd. for C₁₈H₁₄F₃N403 [M+H]⁺ 391.1, found391.1.

Example 135. Synthesis of Compound 159

To a mixture of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg,0.2 mmol), (2-methyloxazol-4-yl)methanol (45.82 mg, 0.41 mmol) and PPh₃(106.26 mg, 0.41 mmol) in THF (2 mL) was added the DIAD (81.92 mg, 0.41mmol), and the mixture was stirred at 20° C. under N₂ for 16 hours. Thereaction was diluted with sat.NH₄Cl (10 mL), and the mixture wasextracted with EtOAc (10 mL×2). Then the combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=0 to 40% to 70%) to give theproduct (36.56 mg, 0.09 mmol, 46% yield) as a solid.

¹H NMR (CDCl₃, 400 MHz) δ_(H)=8.00 (d, 2H), 7.66 (s, 1H), 7.50-7.45 (m,2H), 7.32 (d, 2H), 5.07 (s, 2H), 2.43 (s, 3H). LCMS R_(t)=1.18 min in 2min chromatography, MS ESI calcd. for C18H13F₃N304 [M+H]⁺ 392.1, found392.0.

Example 136. Synthesis of Compound 160

To a mixture of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg,0.2 mmol), (3-methylisoxazol-5-yl)methanol (45.82 mg, 0.41 mmol) andPPh₃ (106.26 mg, 0.41 mmol) in THF (1 mL) was added the DIAD (81.92 mg,0.41 mmol), and the mixture was stirred at 20° C. under N₂ for 16 hours.The reaction was diluted with sat.NH₄Cl (10 mL), and the mixture wasextracted with EtOAc (10 mL×2). Then the combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=20% to 70%) to give theproduct (43.59 mg, 0.11 mmol, 55% yield) as solid. ¹H NMR (DMSO-d₆ 400MHz) δ_(H)=8.17 (d, 2H), 7.89-7.81 (m, 2H), 7.48 (d, 2H), 6.50 (s, 1H),5.23 (s, 2H), 2.20 (s, 3H). LCMS R_(t)=1.21 min in 2.0 minchromatography, MS ESI calcd. for C₁₈H₁₃F₃N₃O₄ [M+H]⁺ 392.1, found392.0.

Example 137. Synthesis of Compound 161

To a mixture of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg,0.20 mmol), PPh₃ (106.26 mg, 0.41 mmol) and(3-methyl-1,2,4-oxadiazol-5-yl)methanol (46.23 mg, 0.41 mmol) in THF (1mL) was added DIAD (81.92 mg, 0.41 mmol). The mixture was stirred at 20°C. under N₂ for 16 hours. The mixture was diluted with NH₄Cl (20 mL),and extracted with EtOAc (20 mL×2). The combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified by Prep-HPLC(Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN;52-72% B over 7 minutes) to give the product (34.48 mg, 85.80 μmol, 42%yield) as a solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.13 (d, 2H),7.95-7.81 (m, 2H), 7.48 (d, 2H), 5.49 (s, 2H), 2.32 (s, 3H). LCMSR_(t)=1.17 min in 2 min chromatography, MS ESI calcd. for C₁₇H₁₂F₃N₄O₄[M+H]⁺ 393.1, found 393.0.

Example 138. Synthesis of Compound 162

To a mixture of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg,0.20 mmol), PPh₃ (106.26 mg, 0.41 mmol) and(5-methyl-1,2,4-oxadiazol-3-yl)methanol (46.23 mg, 0.41 mmol) in THF (1mL) was added DIAD (81.92 mg, 0.41 mmol). The mixture was stirred at 20°C. under N₂ for 16 hours. The reaction was diluted with sat.NH₄Cl (20mL), and the mixture was extracted with EtOAc (15 mL×2). Then thecombined organic phase was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by Prep-HPLC(Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10mM NH₄HCO₃) and B=CH₃CN; 52-72% B over 6 minutes) to give the product(18.43 mg, 46.80 mmol, 23% yield) as a solid. ¹H NMR DMSO-d₆ 400 MHzδ_(H)=8.14 (d, 2H), 7.95-7.80 (m, 2H), 7.48 (d, 2H), 5.26 (s, 2H), 2.56(s, 3H). LCMS R_(t)=1.16 min in 2 min chromatography, MS ESI calcd. forC₁₇H₁₂F₃N₄O₄ [M+H]⁺ 393.1, found 393.0.

Example 139. Synthesis of Compound 163

A mixture of (4-methyl-1,2,4-triazol-3-yl)methanol (45.83 mg, 0.41mmol), 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60mg, 0.20 mmol), PPh₃ (106.26 mg, 0.41 mmol) and DIAD (81.92 mg, 0.41mmol) in THF (3 mL) was stirred at 20 ° C. under N₂ for 16 hours. Thereaction was diluted with sat.NH₄Cl (10 mL), and the mixture wasextracted with EtOAc (10 mL×2). Then the combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified by Prep-HPLC(Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN;32-47% B over 8 minutes) to give the impure product. The impure productwas triturated from i-Pr₂O (10 mL) and purified by Prep-HPLC (WatersXbridge (150 mm×25 mm, 5 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 33-63% Bover 6 minutes) to give the product (16.59 mg, 41.1 μmol, 20% yield) asa solid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.48 (s, 1H), 8.14 (d, 2H), 7.88(d, 1H), 7.81 (d, 1H), 7.48 (d, 2H), 5.30 (s, 2H), 3.79 (s, 3H). LCMSR_(t)=1.10 min in 2.0 min chromatography, MS ESI calcd. for C17H13F₃N503[M+H]⁺ 392.1, found 391.9.

Example 140. Synthesis of Compound 164

A mixture of (2-methyl-1,2,4-triazol-3-yl)methanol (45.83 mg, 0.41mmol), 5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60mg, 0.20 mmol), PPh₃ (106.26 mg, 0.41 mmol) and DIAD (81.92 mg, 0.41mmol) in THF (3 mL) was stirred at 20° C. under N₂ for 16 hours. Thereaction was diluted with sat.NH₄Cl (10 mL), and the mixture wasextracted with EtOAc (10 mL×2). Then the combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=10% to 40%) to give impureproduct. The impure product was purified by Prep-HPLC (Xbridge BEH C18(250 mm×50 mm, 10 μm) A=H₂O (10 mM NH₄HCO₃) and B=CH₃CN; 38-68% B over 9minutes) to give the product (20.82 mg, 52.6 μmol, 26% yield) as asolid. ¹H NMR (DMSO-d₆ 400 MHz) δ_(H)=8.12 (d, 2H), 7.90-7.86 (m, 1H),7.84-7.79 (m, 2H), 7.48 (d, 2H), 5.34 (s, 2H), 4.01 (s, 3H). LCMSR_(t)=1.09 min in 2.0 min chromatography, MS ESI calcd. for C17H13F₃N503[M+H]⁺ 392.1, found 392.0.

Example 141. Synthesis of Compound 165

A mixture of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (60 mg,0.20 mmol), 1H-pyrazol-4-ylmethanol (39.74 mg, 0.41 mmol), PPh₃ (106.26mg, 0.41 mmol) and DIAD (81.92 mg, 0.41 mmol) in THF (3 mL) was stirredat 20° C. under N₂ for 16 hours. The reaction was diluted with sat.NH₄Cl(10 mL), and the mixture was extracted with EtOAc (10 mL×2). Then thecombined organic phase was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by Prep-HPLC (Waters Xbridge (150 mm×25 mm, 5 μm) A=H₂O (10mM NH₄HCO₃) and B=CH₃CN; 46-66% B over 6 minutes) to give the product(23.1 mg, 61.4 μmol, 30% yield) as a solid. ¹H NMR (DMSO-d₆ 400 MHz)δ_(H)=12.83 (br s, 1H), 8.22 (d, 2H), 7.87-7.77 (m, 3H), 7.59 (s, 1H),7.50 (d, 2H), 4.97 (s, 2H). LCMS R_(t)=1.13 min in 2.0 minchromatography, MS ESI calcd. for C₁₇H₁₂F₃N₄O₃ [M+H]⁺ 377.1, found377.1.

Example 142. Synthesis of Compound 166

A mixture of5[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (150 mg,0.51 mmol), chloro(methylsulfanyl)methane (244.55 mg, 2.53 mmol) andDIPEA (0.44 mL, 2.53 mmol) in MeCN (10 mL) was stirred at 50° C. for 12hours. After cooling to r.t., the mixture was diluted with H₂O (30 mL),and the mixture was extracted with EtOAc (50 mL×2). The combined organicphase was washed with water (30 mL) and brine (30 mL), dried overNa₂SO₄, filtered and concentrated to give the crude product. The crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=0% to 15% to 30%) to give the product (110 mg, 0.31 mmol, 61% yield)as a solid. LCMS R_(t)=0.97 min in 1.5 min chromatography, MS ESI calcd.for C₁₅H₁₂F₃N₂O₃S [M+H]⁺ 357.0, found 357.0. To a mixture of3-(methylsulfanylmethyl)-5-[4-(trifluoromethoxy)phenyl]oxazolo[4,5-b]pyridinone (60 mg, 0.17 mmol) in THF (10 mL) was added m-CPBA (102.56 mg, 0.51mmol) at 0° C., then the mixture was stirred at 0° C. for 3 hours. Themixture was quenched with sat. Na₂CO₃ (10 mL), then the mixture wasextracted with EtOAc (30 mL×2). The combined organic phase was washedwith brine (15 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by Prep-TLC (silicagel, PE : EtOAc=1:1) to give the product (52.19 mg, 134.4 μmol, 80%yield) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ_(H)=7.99 (d, 2H), 7.62-7.55(m, 2H), 7.33 (d, 2H), 5.23 (s, 2H), 3.17 (s, 3H). LCMS R_(t)=1.11 minin 2.0 min chromatography, MS ESI calcd. for C₁₅H₁₂F₃N₂O₅S [M+H]⁺ 389.0,found 388.9.

Example 143. Synthesis of Compound 167

To a mixture of5-[4-(trifluoromethoxy)phenyl]-3H-oxazolo[4,5-b]pyridin-2-one (100 mg,0.34 mmol), (3-methyl-1H-pyrazol-4-yl)methanol (75.71 mg, 0.68 mmol) andPPh₃ (265.65 mg, 1.01 mmol) in THF (3 mL) was added DIAD (204.8 mg, 1.01mmol). The mixture was stirred at 20° C. for 16 hours. The reaction wasquenched with sat.NH₄Cl (10 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with brine (10mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by prep-HPLC (Xbridge (150 mm×30mm, 10 μm) A=H₂O (0.05% NH₄OH) and B=CH₃CN; 48-78% B over 7 minutes) togive the product (33.96 mg, 87.00 μmol, 26% yield) as a solid. ¹H NMR(CDCl₃, 400 MHz) δ_(H)=10.00-9.24 (m, 1H), 8.02 (d, 2H), 7.79 (s, 1H),7.50-7.41 (m, 2H), 7.34 (d, 2H), 5.02 (s, 2H), 2.49 (s, 3H). LCMSR_(t)=1.12 min in 2.0 min chromatography, MS ESI calcd. for C₁₈H₁₄F₃N₄O₃[M+H]⁺ 391.1, found 391.0.

Example 144: Efficacy of Exemplary Compounds in the Modulation of LateSodium Current (INaL)

Functional characterization of exemplary compounds to modulate INaLexpressed by the Nav1.6 voltage-gated sodium channel was accomplishedusing the PatchXpress™ high throughput electrophysiology platform(Molecular Devices, Sunnyvale, Calif.). HEK-293 cells expressingrecombinant, human Nav1.6 (hNav1.6)were grown in DMEM/high-glucoseDulbecco's modified, 10% FBS, 2 mM sodium pyruvate, 10 mM HEPES and 400μg/mL G418. Cells were grown to 50%-80% confluency prior to harvesting.Trypsinized cells were washed, allowed to recover for 1 hour and thenresuspended in extracellular recording solution at a concentration of1×10⁶ cells/ml. The onboard liquid handling facility of the

PatchXpress was used for dispensing cells and applying test compounds.Nav late currents were evoked by the application of 300 nM ATX-II. INaLwas evoked by depolarizing pulses to 0 mV for 200 ms from anon-inactivating holding potential (e.g., −120 mV) at a frequency of 0.1Hz. INaL amplitude and stability were determined by analyzing the meancurrent amplitude over the final 20 ms of thetest pulse. Followingsteady state block with exemplary compounds (e.g., as described herein),a Na⁺ free solution containing an impermeant cation (e.g., Choline orNDMG) was added to confirm the identify of the sodium current. Percentsteady-state inhibition of INaL was calculated as:[(INaL_compound)/(INaL_control)]*100, where INaL_compound andINaL_control represent INaL recorded in the presence or absence ofcompound, respectively.

Results from this assay relating to percent inhibition of INaL athNav1.5 (measured using procedure similar to described above but usingHEK-293 cells expressing recombinant, human Nav1.5 (hNav1.5) at 1 μM aresummarized in Table 1 below. In this table, “A” indicates inhibition ofless than 30%; “B” indicates inhibition of between about 30% to about70%; and “C” indicates inhibition of greater than 70%.

TABLE 1 INaL v1.6 Compound (1 μM, % Inhibition) 1 C 2 B 3 C 4 C 5 C 6 B7 C 8 A 9 A 10 C 11 C 12 C 13 C 14 B 15 A 16 A 17 B 18 A 19 C 20 B 21 B22 A 23 A 24 A 25 C 26 C 27 B 28 C 29 A 30 B 31 B 32 B 33 C 34 B 35 C 36A 37 B 38 B 39 C 40 B 41 A 42 A 43 A 44 A 45 A 46 A 47 A 48 B 49 A 50 B51 B 52 B 53 C 54 B 55 B 56 C 57 C 58 C 59 B 61 C 62 C 64 C 65 B 66 C 67C 68 C 69 C 70 B 71 A 72 C 73 C 75 C 76 C 77 B 78 C 79 B 80 B 81 C 84 C85 B 86 C 87 B 88 A 89 C 90 B 91 B 92 A 93 C 96 B 97 C 98 B 99 C 100 C101 C 102 C 103 C 104 C 105 C 106 C 107 B 108 B 109 C 110 B 111 B 112 C113 B 114 A 115 A 116 C 117 C 118 A 119 C 120 C 121 B 122 A 123 C 124 C125 A 126 B 127 C 128 B 129 C 130 A 131 C 132 C 133 C 134 C 135 B 136 A137 A 138 B 139 B 140 B 141 B 142 A 143 C 144 A 145 A 146 C 147 C 148 A149 C 150 B 151 C 152 A 153 B 154 C 155 C 156 C 157 B 158 B 159 C 160 C161 C 162 C 163 A 164 B 165 B 166 B 167 A

Equivalents and Scope

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub—range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein.

The scope of the present embodiments described herein is not intended tobe limited to the above Description, but rather is as set forth in theappended claims. Those of ordinary skill in the art will appreciate thatvarious changes and modifications to this description may be madewithout departing from the spirit or scope of the present invention, asdefined in the following claims.

1. A method of treating a neurological disorder or a psychiatricdisorder, wherein the method comprises administering to a subject inneed thereof a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: each of X, Y,and Z is independently N or CR′; M is O, C(R^(2a))(R^(2b)), orN(R^(2c)); A is aryl or heteroaryl (e.g., 6-membered aryl orheteroaryl), wherein aryl and heteroaryl are substituted by one or moreR³; R′ is hydrogen, alkyl, —OR^(c), or halogen; R¹ is hydrogen, alkyl,carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more R⁴; each ofR^(2a), R^(2b), and R^(2c) is independently hydrogen or alkyl, whereinalkyl is optionally substituted by one or more R⁴; each R³ isindependently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or—OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl are optionallysubstituted with one or more R⁵; each of R⁴ and R⁵ is independentlydeuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,oxo, cyano, nitro, —OR^(c), —N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), or—C(O)N(R^(d))₂, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁷; each R^(c) isindependently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl, wherein each alkyl is optionallysubstituted by one or more R⁶; or two R^(d), taken together with theatoms to which they are attached, form a ring; each R⁶ is independentlyalkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH; and eachR⁷ is independently alkyl, halo, or oxo.
 2. A method of treating aneurological disorder or a psychiatric disorder, wherein the methodcomprises administering to a subject in need thereof a compound ofFormula (I-1):

or a pharmaceutically acceptable salt thereof, wherein: each of X, Y,and Z is independently N or CR′; M is O, C(R^(2a))(R^(2b)), orN(R^(2c)); A is aryl or heteroaryl (e.g., 6-membered aryl orheteroaryl), wherein aryl and heteroaryl are substituted by one or moreR³; R′ is hydrogen, alkyl, —OR^(c), or halogen; R¹ is hydrogen, alkyl,carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more R⁴; each ofR^(2a), R^(2b), and R^(2c) is independently hydrogen or alkyl, whereinalkyl is optionally substituted by one or more R⁴; each R³ isindependently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or—OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl are optionallysubstituted with one or more R⁵; each of R⁴ and R⁵ is independentlydeuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,oxo, cyano, nitro, —OR^(c), —N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c),—S(O)₂—R^(e), —S(O)₂N(R^(d))₂, or —C(O)N(R^(d))₂, wherein alkyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁷; each R^(c) is independently hydrogen,alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl,carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substitutedby one or more R⁶; each R^(d) is independently hydrogen or alkyl,wherein each alkyl is optionally substituted by one or more R⁶; or twoR^(d), taken together with the atoms to which they are attached, form aheterocyclyl optionally substituted with —OH, alkoxy, or alkyloptionally substituted with alkoxy; each R^(e) is alkyl; each R⁶ isindependently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or—OH; and each R⁷ is independently alkyl, halo, oxo, —C(O)R^(c), or—C(O)OR^(c); wherein the compound is not one of the following:

and a pharmaceutically acceptable salt thereof. 3-24. (canceled)
 25. Themethod of claim 2, wherein the compound of Formula (I-1) is a compoundof Formula (I-2):

or a pharmaceutically acceptable salt thereof, wherein: each of X, Y,and Z is independently N or CR′; M is O or C(R^(2a))(R^(2b)); R′ ishydrogen, alkyl, —OR^(c), or halogen; R¹ is hydrogen, alkyl,carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more R⁴; each ofR^(2a) and R^(2b) is independently hydrogen or alkyl, wherein alkyl isoptionally substituted by one or more R⁴; each R^(3a) is independentlyalkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR^(c),wherein alkyl, carbocyclyl, and heterocyclyl are optionally substitutedwith one or more R⁵; each of R⁴ and R⁵ is independently deuterium,alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro,—C(O)N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), —S(O)₂—R^(e), —S(O)₂N(R^(d))₂,or —OR^(c), wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁷; each R^(c) isindependently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl optionally substituted with one or morehalogen; or two R^(d), taken together with the atoms to which they areattached, form a heterocyclyl optionally substituted with-OH, alkoxy, oralkyl optionally substituted with alkoxy; each R^(e) is alkyl; each R⁶is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro,or —OH; each R⁷ is independently alkyl, oxo, halo, —C(O)R^(c), or—C(O)OR^(c); n is 0, 1, 2, 3, or
 4. 26. The method of claim 25, whereinthe compound of formula I-2 is a compound of formula I-3:

or a pharmaceutically acceptable salt thereof.
 27. The method of claim25, wherein the compound of formula I-2 is a compound of formula I-4:

or a pharmaceutically acceptable salt thereof.
 28. The method of claim25, wherein the compound of formula I-2 is a compound of formula I-5:

or a pharmaceutically acceptable salt thereof.
 29. The method of claim25, wherein the compound of formula I-2 is a compound of formula I-6:

or a pharmaceutically acceptable salt thereof. 30-35. (canceled)
 36. Themethod of claim 25, wherein the compound of Formula (I-1) is a compoundof Formula (I-7):

or a pharmaceutically acceptable salt thereof, wherein: each of X, Y,and Z is independently N or CR′; M is N(R^(2c)); R′ is hydrogen, alkyl,—OR^(c), or halogen; R¹ is hydrogen, alkyl, carbocyclyl, orheterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁴; each of R^(2c) isindependently hydrogen or alkyl, wherein alkyl is optionally substitutedby one or more R⁴; each R^(3a) is independently alkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OR^(c), wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁵; each of R⁴ and R⁵ is independently deuterium, alkyl,carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro,—C(O)N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), —S(O)₂—R^(e), —S(O)₂N(R^(d))₂,or —OR^(c), wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁷; each R^(c) isindependently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl optionally substituted with one or morehalogen; or two R^(d), taken together with the atoms to which they areattached, form a heterocyclyl optionally substituted with —OH, alkoxy,or alkyl optionally substituted with alkoxy; each R^(e) is alkyl; eachR⁶ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OH; each R⁷ is independently alkyl, oxo, halo, —C(O)R^(c), or—C(O)OR^(c); n is 0, 1, 2, 3, or 4; wherein the compound is not one ofthe following:

and a pharmaceutically acceptable salt thereof. 37-41. (canceled) 41.The method of claim 1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 42. A compound of Formula(I-1):

or a pharmaceutically acceptable salt thereof, wherein: each of X, Y,and Z is independently N or CR′; M is O, C(R^(2a))(R^(2b)), orN(R^(2c)); A is aryl or heteroaryl (e.g., 6-membered aryl orheteroaryl), wherein aryl and heteroaryl are substituted by one or moreR³; R′ is hydrogen, alkyl, —OR^(c), or halogen; R¹ is hydrogen, alkyl,carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more R⁴; each ofR^(2a), R^(2b), and R^(2c) is independently hydrogen or alkyl, whereinalkyl is optionally substituted by one or more R⁴; each R³ isindependently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or—OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl are optionallysubstituted with one or more R⁵; each of R⁴ and R⁵ is independentlydeuterium, alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,oxo, cyano, nitro, —OR^(c), —N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c),—S(O)₂—R^(e), —S(O)₂N(R^(d))₂, or —C(O)N(R^(d))₂, wherein alkyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁷; each R^(c) is independently hydrogen,alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein alkyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted by one or more R⁶; each R^(d) is independently hydrogen oralkyl, wherein each alkyl is optionally substituted by one or more R⁶;or two R^(d), taken together with the atoms to which they are attached,form a heterocyclyl optionally substituted with -OH, alkoxy, or alkyloptionally substituted with alkoxy; each R^(e) is alkyl; each R⁶ isindependently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or—OH; and each R⁷ is independently alkyl, halo, oxo, —C(O)R^(c), or—C(O)OR^(c); wherein the compound is not one of the following:

and a pharmaceutically acceptable salt thereof. 43-59. (canceled) 60.The compound of claim 42, wherein the compound of Formula (I-1) is acompound of Formula (I-2):

or a pharmaceutically acceptable salt thereof, wherein: each of X, Y,and Z is independently N or CR′; M is O or C(R^(2a))(R^(2b)); R′ ishydrogen, alkyl, —OR^(c), or halogen; R¹ is hydrogen, alkyl,carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more R⁴; each ofR^(2a) and R^(2b) is independently hydrogen or alkyl, wherein alkyl isoptionally substituted by one or more R⁴; each R^(3a) is independentlyalkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR^(c),wherein alkyl, carbocyclyl, and heterocyclyl are optionally substitutedwith one or more R⁵; each of R⁴ and R⁵ is independently deuterium,alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro,—C(O)N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), —S(O)₂—R^(c), —S(O)₂N(R^(d))₂,or —OR^(c), wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁷; each R^(c) isindependently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl optionally substituted with one or morehalogen; or two R^(d), taken together with the atoms to which they areattached, form a heterocyclyl optionally substituted with —OH, alkoxy,or alkyl optionally substituted with alkoxy; each R^(e) is alkyl; eachR⁶ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OH; each R⁷ is independently alkyl, oxo, halo, —C(O)R^(c), or—C(O)OR^(c); n is 0, 1, 2, 3, or 4, wherein the compound is not one ofthe following:

and a pharmaceutically acceptable salt thereof.
 61. The compound ofclaim 60, wherein the compound of formula I-2 is a compound of formulaI-3:

or a pharmaceutically acceptable salt thereof.
 62. The compound of claim60, wherein the compound of formula I-2 is a compound of formula I-4:

or a pharmaceutically acceptable salt thereof.
 63. The compound of claim60, wherein the compound of formula I-2 is a compound of formula I-5:

or a pharmaceutically acceptable salt thereof.
 64. The compound of claim60, wherein the compound of formula I-2 is a compound of formula I-6:

or a pharmaceutically acceptable salt thereof. 65-72. (canceled)
 73. Thecompound of claim 42, wherein the compound of Formula (I-1) is acompound of Formula (I-7):

or a pharmaceutically acceptable salt thereof, wherein: each of X, Y,and Z is independently N or CR′; M is N(R^(2c)); R′ is hydrogen, alkyl,—OR^(c), or halogen; R¹ is hydrogen, alkyl, carbocyclyl, orheterocyclyl, wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁴; each of R^(2c) isindependently hydrogen or alkyl, wherein alkyl is optionally substitutedby one or more R⁴; each R^(3a) is independently alkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OR^(c), wherein alkyl,carbocyclyl, and heterocyclyl are optionally substituted with one ormore R⁵; each of R⁴ and R⁵ is independently deuterium, alkyl,carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro,—C(O)N(R^(d))₂, —C(O)R^(c), —C(O)OR^(c), —S(O)₂—R^(c), —S(O)₂N(R^(d))₂,or —OR^(c), wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁷; each R^(c) isindependently hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl, orheteroaryl, wherein alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl optionally substituted with one or morehalogen; or two R^(d), taken together with the atoms to which they areattached, form a heterocyclyl optionally substituted with-OH, alkoxy, oralkyl optionally substituted with alkoxy; each R^(e) is alkyl; each R⁶is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro,or —OH; each R⁷ is independently alkyl, oxo, halo, —C(O)R^(c), or—C(O)OR^(c); n is 0, 1, 2, 3, or 4; wherein the compound is not one ofthe following:

and a pharmaceutically acceptable salt thereof 74-78. (canceled)
 79. Thecompound of claim 42, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 80. A pharmaceuticalcomposition comprising a compound of claim 42, or pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 81.The method of claim 1, wherein the method comprises administering thepharmaceutical composition of claim
 80. 82. A method of treating aneurological disorder or a psychiatric disorder, wherein the methodcomprises administering to a subject in need thereof the compound ofclaim 42.